TY  - JOUR
AU  - Sharmin, Dishary
AU  - Divović, Branka
AU  - Ping, Xingjie
AU  - Cerne, Rok
AU  - Smith, Jodi L.
AU  - Rezvanian, Sepideh
AU  - Mondal, Prithu
AU  - Michelle, Meyer Jean
AU  - Kiley, Molly E.
AU  - Arnold, Leggy A.
AU  - Mian, Md Yeunus
AU  - Pandey, Kamal P.
AU  - Jin, Xiaoming
AU  - Mitrović, Jelena
AU  - Đorović, Đorđe
AU  - Lippa, Arnold
AU  - Cook, James M.
AU  - Golani, Lalit K.
AU  - Scholze, Petra
AU  - Savić, Miroslav
AU  - Witkin, Jeffrey M.
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5505
AB  - KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.
PB  - American Chemical Society
T2  - ACS Chemical Neuroscience
T1  - New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy
VL  - 15
IS  - 3
SP  - 517
EP  - 526
DO  - 10.1021/acschemneuro.3c00555
ER  - 

@article{
author = "Sharmin, Dishary and Divović, Branka and Ping, Xingjie and Cerne, Rok and Smith, Jodi L. and Rezvanian, Sepideh and Mondal, Prithu and Michelle, Meyer Jean and Kiley, Molly E. and Arnold, Leggy A. and Mian, Md Yeunus and Pandey, Kamal P. and Jin, Xiaoming and Mitrović, Jelena and Đorović, Đorđe and Lippa, Arnold and Cook, James M. and Golani, Lalit K. and Scholze, Petra and Savić, Miroslav and Witkin, Jeffrey M.",
year = "2024",
abstract = "KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.",
publisher = "American Chemical Society",
journal = "ACS Chemical Neuroscience",
title = "New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy",
volume = "15",
number = "3",
pages = "517-526",
doi = "10.1021/acschemneuro.3c00555"
}

Sharmin, D., Divović, B., Ping, X., Cerne, R., Smith, J. L., Rezvanian, S., Mondal, P., Michelle, M. J., Kiley, M. E., Arnold, L. A., Mian, M. Y., Pandey, K. P., Jin, X., Mitrović, J., Đorović, Đ., Lippa, A., Cook, J. M., Golani, L. K., Scholze, P., Savić, M.,& Witkin, J. M.. (2024). New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy. in ACS Chemical Neuroscience
American Chemical Society., 15(3), 517-526.
https://doi.org/10.1021/acschemneuro.3c00555

Sharmin D, Divović B, Ping X, Cerne R, Smith JL, Rezvanian S, Mondal P, Michelle MJ, Kiley ME, Arnold LA, Mian MY, Pandey KP, Jin X, Mitrović J, Đorović Đ, Lippa A, Cook JM, Golani LK, Scholze P, Savić M, Witkin JM. New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy. in ACS Chemical Neuroscience. 2024;15(3):517-526.
doi:10.1021/acschemneuro.3c00555 .

Sharmin, Dishary, Divović, Branka, Ping, Xingjie, Cerne, Rok, Smith, Jodi L., Rezvanian, Sepideh, Mondal, Prithu, Michelle, Meyer Jean, Kiley, Molly E., Arnold, Leggy A., Mian, Md Yeunus, Pandey, Kamal P., Jin, Xiaoming, Mitrović, Jelena, Đorović, Đorđe, Lippa, Arnold, Cook, James M., Golani, Lalit K., Scholze, Petra, Savić, Miroslav, Witkin, Jeffrey M., "New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy" in ACS Chemical Neuroscience, 15, no. 3 (2024):517-526,
https://doi.org/10.1021/acschemneuro.3c00555 . .

TY  - JOUR
AU  - Pandey, Kamal P.
AU  - Divović, Branka
AU  - Rashid, Farjana
AU  - Golani, Lalit K.
AU  - Cerne, Rok
AU  - Zahn, Nicolas M.
AU  - Meyer, Michelle Jean
AU  - Arnold, Leggy A.
AU  - Sharmin, Dishary
AU  - Mian, Md Yeunus
AU  - Smith, Jodi L.
AU  - Ping, Xingjie
AU  - Jin, Xiaoming
AU  - Lippa, Arnold
AU  - Tiruveedhula, Phani Babu V. V. N.
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Witkin, Jeffrey M.
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5605
AB  - To provide back-up compounds to support the development of the GABAA receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPPIII-34 and KPP-III-51), or substituting a Br atom for the ethynyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice [maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures], whereas KPPIII-51 did not. Although all compounds were orally bioavailable, structural changes reduced the plasma and brain (FR-II-60 and KPP-III-51) exposures relative to KRM-II-81. Oral administration of each compound produced dose-dependent increases in the latency for both clonic and tonic seizures and the lethality induced by pentylenetetrazol (PTZ) in mice. Since KPP-III-34 produced the highest brain area under the curve (AUC) exposures, it was selected for further profiling. Oral administration of KPP-III-34 suppressed seizures in corneal-kindled mice, hippocampal paroxysmal discharges in mesial temporal lobe epileptic mice, and PTZ-induced convulsions in rats. Only transient sensorimotor impairment was observed in mice, and doses of KPP-III-34 up to 500 mg/kg did not produce impairment in rats. Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to a1His102 compared with the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. Overall, these findings document the oral bioavailability and anticonvulsant efficacy of three novel analogs of KRM-II-81 with reduced sedative effects. SIGNIFICANCE STATEMENT A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is moving into clinical development. Three new analogs were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low sensorimotor impairment. KPP-III-34 demonstrated efficacy in models of pharmacoresistant epilepsy. Docking studies demonstrated a low propensity for compound binding to the a1His102 residue implicated in sedation. Thus, three additional structures have been added to the list of non-sedating imidazodiazepine anticonvulsants that could serve as backups in the clinical development of KRM-II-81. Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.
PB  - American Society for Pharmacology and Experimental Therapy (ASPET)
T2  - Journal of Pharmacology and Experimental Therapeutics
T1  - Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation
VL  - 385
IS  - 1
SP  - 50
EP  - 61
DO  - 10.1124/jpet.122.001362
ER  - 

@article{
author = "Pandey, Kamal P. and Divović, Branka and Rashid, Farjana and Golani, Lalit K. and Cerne, Rok and Zahn, Nicolas M. and Meyer, Michelle Jean and Arnold, Leggy A. and Sharmin, Dishary and Mian, Md Yeunus and Smith, Jodi L. and Ping, Xingjie and Jin, Xiaoming and Lippa, Arnold and Tiruveedhula, Phani Babu V. V. N. and Cook, James M. and Savić, Miroslav and Witkin, Jeffrey M.",
year = "2023",
abstract = "To provide back-up compounds to support the development of the GABAA receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPPIII-34 and KPP-III-51), or substituting a Br atom for the ethynyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice [maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures], whereas KPPIII-51 did not. Although all compounds were orally bioavailable, structural changes reduced the plasma and brain (FR-II-60 and KPP-III-51) exposures relative to KRM-II-81. Oral administration of each compound produced dose-dependent increases in the latency for both clonic and tonic seizures and the lethality induced by pentylenetetrazol (PTZ) in mice. Since KPP-III-34 produced the highest brain area under the curve (AUC) exposures, it was selected for further profiling. Oral administration of KPP-III-34 suppressed seizures in corneal-kindled mice, hippocampal paroxysmal discharges in mesial temporal lobe epileptic mice, and PTZ-induced convulsions in rats. Only transient sensorimotor impairment was observed in mice, and doses of KPP-III-34 up to 500 mg/kg did not produce impairment in rats. Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to a1His102 compared with the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. Overall, these findings document the oral bioavailability and anticonvulsant efficacy of three novel analogs of KRM-II-81 with reduced sedative effects. SIGNIFICANCE STATEMENT A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is moving into clinical development. Three new analogs were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low sensorimotor impairment. KPP-III-34 demonstrated efficacy in models of pharmacoresistant epilepsy. Docking studies demonstrated a low propensity for compound binding to the a1His102 residue implicated in sedation. Thus, three additional structures have been added to the list of non-sedating imidazodiazepine anticonvulsants that could serve as backups in the clinical development of KRM-II-81. Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.",
publisher = "American Society for Pharmacology and Experimental Therapy (ASPET)",
journal = "Journal of Pharmacology and Experimental Therapeutics",
title = "Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation",
volume = "385",
number = "1",
pages = "50-61",
doi = "10.1124/jpet.122.001362"
}

Pandey, K. P., Divović, B., Rashid, F., Golani, L. K., Cerne, R., Zahn, N. M., Meyer, M. J., Arnold, L. A., Sharmin, D., Mian, M. Y., Smith, J. L., Ping, X., Jin, X., Lippa, A., Tiruveedhula, P. B. V. V. N., Cook, J. M., Savić, M.,& Witkin, J. M.. (2023). Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation. in Journal of Pharmacology and Experimental Therapeutics
American Society for Pharmacology and Experimental Therapy (ASPET)., 385(1), 50-61.
https://doi.org/10.1124/jpet.122.001362

Pandey KP, Divović B, Rashid F, Golani LK, Cerne R, Zahn NM, Meyer MJ, Arnold LA, Sharmin D, Mian MY, Smith JL, Ping X, Jin X, Lippa A, Tiruveedhula PBVVN, Cook JM, Savić M, Witkin JM. Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation. in Journal of Pharmacology and Experimental Therapeutics. 2023;385(1):50-61.
doi:10.1124/jpet.122.001362 .

Pandey, Kamal P., Divović, Branka, Rashid, Farjana, Golani, Lalit K., Cerne, Rok, Zahn, Nicolas M., Meyer, Michelle Jean, Arnold, Leggy A., Sharmin, Dishary, Mian, Md Yeunus, Smith, Jodi L., Ping, Xingjie, Jin, Xiaoming, Lippa, Arnold, Tiruveedhula, Phani Babu V. V. N., Cook, James M., Savić, Miroslav, Witkin, Jeffrey M., "Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation" in Journal of Pharmacology and Experimental Therapeutics, 385, no. 1 (2023):50-61,
https://doi.org/10.1124/jpet.122.001362 . .

TY  - JOUR
AU  - Mitrović, Jelena
AU  - Divović-Matović, Branka
AU  - Knutson, Daniel E.
AU  - Petković, Miloš
AU  - Đorović, Đorđe
AU  - Ranđelović, Danijela V.
AU  - Dobričić, Vladimir
AU  - Đoković, Jelena
AU  - Lunter, Dominique J.
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4434
AB  - Preclinical development of deuterated pyrazoloquinolinone ligands, promising drug candidates for various neuropsychiatric disorders, was hindered by unusually low solubility in water and oils. DK-I-60-3 (7-methoxy-d3- 2-(4-methoxy-d3-phenyl)-2,5-dihydro-3Hpyrazolo[4,3-c]quinolin-3-one) is one of such pyrazoloquinolinones, and we recently reported about increased oral bioavailability of its nanocrystal formulation (NC). Lipid nano- particles (LNP) with a high concentration of lecithin, which enhances loading capacity of the lipid matrix, may give rise to further improvement. After preformulation studies by differential scanning calorimetry and polarized light microscopy, LNP were prepared by the hot high pressure homogenization, and characterized in terms of particle size, morphology, and encapsulation efficacy. The layered structure visible on atomic force micrographs was confirmed by nuclear magnetic resonance. Obtained formulations were desirably stable, with small particle size (<100 nm), and high encapsulation efficacy (>99 %). Lecithin was partially fluid and most probably located in the outer shell of the particle, together with DK-I-60-3. While the hydrophobic part of polysorbate 80 was completely immobilized, its hydrophilic part was free in the aqueous phase. In oral neuropharmacokinetic study in rats, an around 1.5-fold increase of area under the curve with LNP compared to NC was noticed both in brain and plasma. In bioavailability study, F value of LNP (34.7 ± 12.4 %) was 1.4-fold higher than of NC (24.5 ± 7.8 %); however, this difference did not reach statistical significance. Therefore, employment of LNP platform in preclinical formulation of DK-I-60-3 imparted an incremental improvement of its physicochemical as well as pharmacokinetic behavior.
PB  - Elsevier B.V.
T2  - International Journal of Pharmaceutics
T1  - High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances
VL  - 633
DO  - 10.1016/j.ijpharm.2023.122613
ER  - 

@article{
author = "Mitrović, Jelena and Divović-Matović, Branka and Knutson, Daniel E. and Petković, Miloš and Đorović, Đorđe and Ranđelović, Danijela V. and Dobričić, Vladimir and Đoković, Jelena and Lunter, Dominique J. and Cook, James M. and Savić, Miroslav and Savić, Snežana",
year = "2023",
abstract = "Preclinical development of deuterated pyrazoloquinolinone ligands, promising drug candidates for various neuropsychiatric disorders, was hindered by unusually low solubility in water and oils. DK-I-60-3 (7-methoxy-d3- 2-(4-methoxy-d3-phenyl)-2,5-dihydro-3Hpyrazolo[4,3-c]quinolin-3-one) is one of such pyrazoloquinolinones, and we recently reported about increased oral bioavailability of its nanocrystal formulation (NC). Lipid nano- particles (LNP) with a high concentration of lecithin, which enhances loading capacity of the lipid matrix, may give rise to further improvement. After preformulation studies by differential scanning calorimetry and polarized light microscopy, LNP were prepared by the hot high pressure homogenization, and characterized in terms of particle size, morphology, and encapsulation efficacy. The layered structure visible on atomic force micrographs was confirmed by nuclear magnetic resonance. Obtained formulations were desirably stable, with small particle size (<100 nm), and high encapsulation efficacy (>99 %). Lecithin was partially fluid and most probably located in the outer shell of the particle, together with DK-I-60-3. While the hydrophobic part of polysorbate 80 was completely immobilized, its hydrophilic part was free in the aqueous phase. In oral neuropharmacokinetic study in rats, an around 1.5-fold increase of area under the curve with LNP compared to NC was noticed both in brain and plasma. In bioavailability study, F value of LNP (34.7 ± 12.4 %) was 1.4-fold higher than of NC (24.5 ± 7.8 %); however, this difference did not reach statistical significance. Therefore, employment of LNP platform in preclinical formulation of DK-I-60-3 imparted an incremental improvement of its physicochemical as well as pharmacokinetic behavior.",
publisher = "Elsevier B.V.",
journal = "International Journal of Pharmaceutics",
title = "High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances",
volume = "633",
doi = "10.1016/j.ijpharm.2023.122613"
}

Mitrović, J., Divović-Matović, B., Knutson, D. E., Petković, M., Đorović, Đ., Ranđelović, D. V., Dobričić, V., Đoković, J., Lunter, D. J., Cook, J. M., Savić, M.,& Savić, S.. (2023). High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances. in International Journal of Pharmaceutics
Elsevier B.V.., 633.
https://doi.org/10.1016/j.ijpharm.2023.122613

Mitrović J, Divović-Matović B, Knutson DE, Petković M, Đorović Đ, Ranđelović DV, Dobričić V, Đoković J, Lunter DJ, Cook JM, Savić M, Savić S. High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances. in International Journal of Pharmaceutics. 2023;633.
doi:10.1016/j.ijpharm.2023.122613 .

Mitrović, Jelena, Divović-Matović, Branka, Knutson, Daniel E., Petković, Miloš, Đorović, Đorđe, Ranđelović, Danijela V., Dobričić, Vladimir, Đoković, Jelena, Lunter, Dominique J., Cook, James M., Savić, Miroslav, Savić, Snežana, "High amount of lecithin facilitates oral delivery of a poorly soluble pyrazoloquinolinone ligand formulated in lipid nanoparticles: Physicochemical, structural and pharmacokinetic performances" in International Journal of Pharmaceutics, 633 (2023),
https://doi.org/10.1016/j.ijpharm.2023.122613 . .

TY  - JOUR
AU  - Ping, Xingjie
AU  - Meyer, Michelle J.
AU  - Zahn, Nicolas M.
AU  - Golani, Lalit K.
AU  - Sharmin, Dishary
AU  - Pandey, Kamal P.
AU  - Revanian, Sepideh
AU  - Mondal, Prithu
AU  - Jin, Xiaoming
AU  - Arnold, Leggy A.
AU  - Cerne, Rok
AU  - Cook, James M.
AU  - Divović, Branka
AU  - Savić, Miroslav
AU  - Lippa, Arnold
AU  - Smith, Jodi L.
AU  - Witkin, Jeffrey M.
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4427
AB  - A series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole known as KRM-II-81) is currently awaiting advancement into the clinic. A deuterated structural analog (D5-KRM-II-81) was made as a potential backup compound and studied here in comparison to KRM-II-81. In the present study, both compounds significantly prevented seizures in mice induced by 6 Hz (44 mA) electrical stimulation without significantly altering motoric function on a rotarod after intraperitoneal administration. Both compounds also significantly prevented clonic seizures, tonic seizures, and lethality induced by pentylenetetrazol in mice when given orally. D5-KRM-II-81 had a slightly longer duration of action against clonic and tonic seizures than KRM-II-81. Oral administration of 100 mg/kg of either KRM-II-81 or D5-KRM-II-81 was significantly less disruptive of sensorimotor function in mice than diazepam (5 mg/kg, p.o.). The present report documents that D5-KRM-II-81 represents another in this series of imidazodiazepines with anticonvulsant activity at doses that do not impair sensorimotor function.
PB  - John Wiley and Sons Inc
T2  - Drug Development Research
T1  - Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog
VL  - 84
IS  - 3
DO  - 10.1002/ddr.22042
ER  - 

@article{
author = "Ping, Xingjie and Meyer, Michelle J. and Zahn, Nicolas M. and Golani, Lalit K. and Sharmin, Dishary and Pandey, Kamal P. and Revanian, Sepideh and Mondal, Prithu and Jin, Xiaoming and Arnold, Leggy A. and Cerne, Rok and Cook, James M. and Divović, Branka and Savić, Miroslav and Lippa, Arnold and Smith, Jodi L. and Witkin, Jeffrey M.",
year = "2023",
abstract = "A series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole known as KRM-II-81) is currently awaiting advancement into the clinic. A deuterated structural analog (D5-KRM-II-81) was made as a potential backup compound and studied here in comparison to KRM-II-81. In the present study, both compounds significantly prevented seizures in mice induced by 6 Hz (44 mA) electrical stimulation without significantly altering motoric function on a rotarod after intraperitoneal administration. Both compounds also significantly prevented clonic seizures, tonic seizures, and lethality induced by pentylenetetrazol in mice when given orally. D5-KRM-II-81 had a slightly longer duration of action against clonic and tonic seizures than KRM-II-81. Oral administration of 100 mg/kg of either KRM-II-81 or D5-KRM-II-81 was significantly less disruptive of sensorimotor function in mice than diazepam (5 mg/kg, p.o.). The present report documents that D5-KRM-II-81 represents another in this series of imidazodiazepines with anticonvulsant activity at doses that do not impair sensorimotor function.",
publisher = "John Wiley and Sons Inc",
journal = "Drug Development Research",
title = "Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog",
volume = "84",
number = "3",
doi = "10.1002/ddr.22042"
}

Ping, X., Meyer, M. J., Zahn, N. M., Golani, L. K., Sharmin, D., Pandey, K. P., Revanian, S., Mondal, P., Jin, X., Arnold, L. A., Cerne, R., Cook, J. M., Divović, B., Savić, M., Lippa, A., Smith, J. L.,& Witkin, J. M.. (2023). Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog. in Drug Development Research
John Wiley and Sons Inc., 84(3).
https://doi.org/10.1002/ddr.22042

Ping X, Meyer MJ, Zahn NM, Golani LK, Sharmin D, Pandey KP, Revanian S, Mondal P, Jin X, Arnold LA, Cerne R, Cook JM, Divović B, Savić M, Lippa A, Smith JL, Witkin JM. Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog. in Drug Development Research. 2023;84(3).
doi:10.1002/ddr.22042 .

Ping, Xingjie, Meyer, Michelle J., Zahn, Nicolas M., Golani, Lalit K., Sharmin, Dishary, Pandey, Kamal P., Revanian, Sepideh, Mondal, Prithu, Jin, Xiaoming, Arnold, Leggy A., Cerne, Rok, Cook, James M., Divović, Branka, Savić, Miroslav, Lippa, Arnold, Smith, Jodi L., Witkin, Jeffrey M., "Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog" in Drug Development Research, 84, no. 3 (2023),
https://doi.org/10.1002/ddr.22042 . .

TY  - THES
AU  - Divović-Matović, Branka
PY  - 2023
UR  - https://eteze.bg.ac.rs/application/showtheses?thesesId=9126
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:29685/bdef:Content/download
UR  - https://plus.cobiss.net/cobiss/sr/sr/bib/107283465
UR  - https://nardus.mpn.gov.rs/handle/123456789/21487
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4975
AB  - Važno mesto u istraživanjima poslednjih godina zauzimaju GABAA receptori (GABAAR) sa α6podjedinicom u pentamernom receptorskom kompleksu. Ovi receptori imaju potencijalno važnuulogu u razvoju trigeminalnog orofacijalnog bola, migreni, neuropsihijatrijskim poremećajima sasenzorno-motornim deficitima kao što su tikovi, Tourette-ov sindrom, određeni simptomishizofrenije, opsesivno-kompulzivni poremećaj i poremećaji pažnje. Otkriveno je mesto vezivanjana α+β- međupovršini GABAAR označeno kao pirazolohinolinonsko (PQ) mesto, zajedno saprvim α6-selektivnim ligandom, PZ-II-029. Zatim je pronađeno još nekoliko PQ liganada kojideluju kao funkcionalno selektivni pozitivni modulatori na PQ mestu α6 GABAA receptora, dokneutralnu modulaciju ostvaruju posredstvom benzodiazepinskog mesta.Najpre smo sproveli eksperimente farmakokinetičke karakterizacije PQ jedinjenja iz tri strukturnegrupe (PZ-II-029 i srodni deuterisani i/ili nitrogenovani analozi DK-I-56-1, RV-I-029, DK-I-60-3i DK-I-86-1; LAU463 i srodni deuterisani i/ili nitrogenovani analozi DK-I-58-1 i DK-II-58-1; iDK-I-87-1) i još pet dodatnih liganada (jedan koji je meta izomer DK-I-87-1 (DK-I-59-1) i četirifluorirana analoga (DK-IV-19-1, DK-IV-20-1, DK-IV-22-1 i MM-I-10)) nakon intraperitonealne,oralne ili intravenske primene. Osim puta primene, faktor varijacije predstavljala je i formulacija(suspenzija, rastvor ili nanoemulzija) kao i soj životinja (C57BL miševi, Wistar i Sprague-Dawleypacovi). Određena je apsolutna oralna biološka raspoloživost, kao i slobodne frakcije u plazmi imozgu dva liganda (PZ-II-029 i DK-I-56-1). Daljim istraživanjem procenjivali smo uticajnavedenih PQ liganada, samih ili u kombinaciji sa diazepamom, na ponašanje adultnih mužjakapacova Wistar i Sprague-Dawley soja, odnosno miševa C57BL soja. Supstanca DK-I-56-1, kojaje na osnovu prethodnih eksperimenata identifikovana kao vodeća molekula, ispitana je nakonhronične konstrikcione povrede infraorbitalnog živca kao modela trigeminalne neuropatije namužjacima pacova Wistar soja. Primena DK-I-56-1 u animalnom modelu trajala je 14 dana počevod prvog dana nakon operacije, a razvoj bolne preosetljivosti ispitivan je von Frey filamentima udefinisanim vremenskim periodima. Farmakokinetički profili i parametri nedvosmisleno ukazujuna optimizaciju i unapređenje farmakokinetike deuterisanih analoga u plazmi i mozgu, prirazličitim putevima primene, kao i pri različitim formulacijama ispitivanog liganda. Obe strategije,deuteracija i fluorovanje, povećale su metaboličku stabilnost, dok su razlike u farmakokineticiizmeđu deuterisanih i fluorovanih analoga bile izražene. Naime, fluorovani analozi pokazujuznačajno zadržavanje u organima za izlučivanje (jetra i bubreg), a uz podatke da pokazuju izvesnucitotoksičnost in vitro na ćelijskim linijama jetre i bubrega, kao i da su efikasnost i funkcionalnaselektivnost za α6+β3- PQ mesto α6-GABAAR smanjeni u poređenju sa deuterisanim ligandima,čini ih manje pogodnim za dalje faze istraživanja. Dakle, strategija deuteracije pokazala sesuperiornom u odnosu na fluorovanje pirazolohinolinona u smislu održavanja α6-GABAAreceptorske selektivnosti uz povećanje metaboličke stabilnosti i biološke raspoloživosti...
AB  - GABAA receptors (GABAARs) containing the α6 subunit (α6-GABAARs) have recently obtainedan important place in research. They play a distinct role in trigeminal orofacial pain, migraine, andneuropsychiatric disorders with sensori-motor gating deficits (such as tic disorders, Tourette’ssyndrome, certain symptoms of schizophrenia, obsessive compulsive disorder and attention deficitdisorders). The binding site at the α+β- interface of GABAARs, designated as thepyrazoloquinolinone (PQ) site, was discovered, along with the first α6-selective ligand, PZ-II-029.Subsequent research led to the development of a series of PQs, as functionally selective positivemodulators at the PQ site of α6-containing GABAARs. PQs are also neutral modulators at thebenzodiazepine site.Firstly, we conducted pharmacokinetic characterization of PQs from three structural groups (PZ-II-029 and related deuterated and/or nitrogenated analogs DK-I-56-1, RV-I-029, DK-I-60-3 andDK-I-86-1; LAU 463 and related deuterated and/or nitrogenated analogs DK-I-58-1 and DK-II-58-1; and DK-I-87-1) and five additional ligands (one meta isomer of DK-I-87-1 (DK-I-59-1) andfour fluorinated analogues (DK-IV-19-1, DK-IV-20-1, DK-IV-22-1 and MM-I-10)), afterintraperitoneal, oral or intravenous administration. Beside the route of administration, formulation(suspension, solution or nanoemulsion) and the animal strain (C57BL mice, Wistar and Sprague-Dawley rats) were additional factors of variation. Absolute oral bioavailability, as well asestimated free fractions in plasma and brain of two ligands (PZ-II-029 and DK-I-56-1), weredetermined. Through further research, we evaluated the influence of PQ ligands, alone or incombination with diazepam, on the behavior of adult male Wistar and Sprague-Dawley rats, orC57BL mice. On the basis of previous experiments, DK-I-56-1 was identified as a "lead"compound and tested after chronic constriction injury of the infraorbital nerve as a model oftrigeminal neuropathy in male Wistar rats. The application of DK-I-56-1 in the animal model lastedfor 14 days starting from the first day after surgery, and the development of pain hypersensitivitywas examined with von Frey filaments in defined time periods. Pharmacokinetic profiles andparameters clearly indicate optimization and improvement of pharmacokinetics of deuteratedanalogues in plasma and brain, with different routes of administration, as well as with differentformulations of the investigated ligand. While the strategy of deuteration and fluorinationincreased metabolic stability, the pharmacokinetic influence on plasma, brain, liver and kidneyexposure was dramatically different. Namely, the fluorinated analogues showed significantretention in the excretory organs (liver and kidney). Also, they exhibited a slightly increasedcytotoxic effect on liver and kidney cell lines in vitro. Efficacy and functional selectivity for theα6+β3- interface (PQ site) of α6-GABAARs was reduced for the fluorinated analogs in comparisonto the deuterated ligands. All these facts make them less suitable for further research. Thus, thedeuteration strategy proved superior to fluorination of these PQs in terms of maintaining α6-GABAAR selectivity while enhancing the metabolic stability and bioavailability. These α6-GABAAR ligands were devoid of observable detrimental effects...
PB  - Универзитет у Београду, Фармацеутски факултет
T2  - Универзитет у Београду
T1  - Farmakološka karakterizacija uticaja deuteracije izabranih pirazolohinolinona kao modulatora GABAA receptora
UR  - https://hdl.handle.net/21.15107/rcub_nardus_21487
ER  - 

@phdthesis{
author = "Divović-Matović, Branka",
year = "2023",
abstract = "Važno mesto u istraživanjima poslednjih godina zauzimaju GABAA receptori (GABAAR) sa α6podjedinicom u pentamernom receptorskom kompleksu. Ovi receptori imaju potencijalno važnuulogu u razvoju trigeminalnog orofacijalnog bola, migreni, neuropsihijatrijskim poremećajima sasenzorno-motornim deficitima kao što su tikovi, Tourette-ov sindrom, određeni simptomishizofrenije, opsesivno-kompulzivni poremećaj i poremećaji pažnje. Otkriveno je mesto vezivanjana α+β- međupovršini GABAAR označeno kao pirazolohinolinonsko (PQ) mesto, zajedno saprvim α6-selektivnim ligandom, PZ-II-029. Zatim je pronađeno još nekoliko PQ liganada kojideluju kao funkcionalno selektivni pozitivni modulatori na PQ mestu α6 GABAA receptora, dokneutralnu modulaciju ostvaruju posredstvom benzodiazepinskog mesta.Najpre smo sproveli eksperimente farmakokinetičke karakterizacije PQ jedinjenja iz tri strukturnegrupe (PZ-II-029 i srodni deuterisani i/ili nitrogenovani analozi DK-I-56-1, RV-I-029, DK-I-60-3i DK-I-86-1; LAU463 i srodni deuterisani i/ili nitrogenovani analozi DK-I-58-1 i DK-II-58-1; iDK-I-87-1) i još pet dodatnih liganada (jedan koji je meta izomer DK-I-87-1 (DK-I-59-1) i četirifluorirana analoga (DK-IV-19-1, DK-IV-20-1, DK-IV-22-1 i MM-I-10)) nakon intraperitonealne,oralne ili intravenske primene. Osim puta primene, faktor varijacije predstavljala je i formulacija(suspenzija, rastvor ili nanoemulzija) kao i soj životinja (C57BL miševi, Wistar i Sprague-Dawleypacovi). Određena je apsolutna oralna biološka raspoloživost, kao i slobodne frakcije u plazmi imozgu dva liganda (PZ-II-029 i DK-I-56-1). Daljim istraživanjem procenjivali smo uticajnavedenih PQ liganada, samih ili u kombinaciji sa diazepamom, na ponašanje adultnih mužjakapacova Wistar i Sprague-Dawley soja, odnosno miševa C57BL soja. Supstanca DK-I-56-1, kojaje na osnovu prethodnih eksperimenata identifikovana kao vodeća molekula, ispitana je nakonhronične konstrikcione povrede infraorbitalnog živca kao modela trigeminalne neuropatije namužjacima pacova Wistar soja. Primena DK-I-56-1 u animalnom modelu trajala je 14 dana počevod prvog dana nakon operacije, a razvoj bolne preosetljivosti ispitivan je von Frey filamentima udefinisanim vremenskim periodima. Farmakokinetički profili i parametri nedvosmisleno ukazujuna optimizaciju i unapređenje farmakokinetike deuterisanih analoga u plazmi i mozgu, prirazličitim putevima primene, kao i pri različitim formulacijama ispitivanog liganda. Obe strategije,deuteracija i fluorovanje, povećale su metaboličku stabilnost, dok su razlike u farmakokineticiizmeđu deuterisanih i fluorovanih analoga bile izražene. Naime, fluorovani analozi pokazujuznačajno zadržavanje u organima za izlučivanje (jetra i bubreg), a uz podatke da pokazuju izvesnucitotoksičnost in vitro na ćelijskim linijama jetre i bubrega, kao i da su efikasnost i funkcionalnaselektivnost za α6+β3- PQ mesto α6-GABAAR smanjeni u poređenju sa deuterisanim ligandima,čini ih manje pogodnim za dalje faze istraživanja. Dakle, strategija deuteracije pokazala sesuperiornom u odnosu na fluorovanje pirazolohinolinona u smislu održavanja α6-GABAAreceptorske selektivnosti uz povećanje metaboličke stabilnosti i biološke raspoloživosti..., GABAA receptors (GABAARs) containing the α6 subunit (α6-GABAARs) have recently obtainedan important place in research. They play a distinct role in trigeminal orofacial pain, migraine, andneuropsychiatric disorders with sensori-motor gating deficits (such as tic disorders, Tourette’ssyndrome, certain symptoms of schizophrenia, obsessive compulsive disorder and attention deficitdisorders). The binding site at the α+β- interface of GABAARs, designated as thepyrazoloquinolinone (PQ) site, was discovered, along with the first α6-selective ligand, PZ-II-029.Subsequent research led to the development of a series of PQs, as functionally selective positivemodulators at the PQ site of α6-containing GABAARs. PQs are also neutral modulators at thebenzodiazepine site.Firstly, we conducted pharmacokinetic characterization of PQs from three structural groups (PZ-II-029 and related deuterated and/or nitrogenated analogs DK-I-56-1, RV-I-029, DK-I-60-3 andDK-I-86-1; LAU 463 and related deuterated and/or nitrogenated analogs DK-I-58-1 and DK-II-58-1; and DK-I-87-1) and five additional ligands (one meta isomer of DK-I-87-1 (DK-I-59-1) andfour fluorinated analogues (DK-IV-19-1, DK-IV-20-1, DK-IV-22-1 and MM-I-10)), afterintraperitoneal, oral or intravenous administration. Beside the route of administration, formulation(suspension, solution or nanoemulsion) and the animal strain (C57BL mice, Wistar and Sprague-Dawley rats) were additional factors of variation. Absolute oral bioavailability, as well asestimated free fractions in plasma and brain of two ligands (PZ-II-029 and DK-I-56-1), weredetermined. Through further research, we evaluated the influence of PQ ligands, alone or incombination with diazepam, on the behavior of adult male Wistar and Sprague-Dawley rats, orC57BL mice. On the basis of previous experiments, DK-I-56-1 was identified as a "lead"compound and tested after chronic constriction injury of the infraorbital nerve as a model oftrigeminal neuropathy in male Wistar rats. The application of DK-I-56-1 in the animal model lastedfor 14 days starting from the first day after surgery, and the development of pain hypersensitivitywas examined with von Frey filaments in defined time periods. Pharmacokinetic profiles andparameters clearly indicate optimization and improvement of pharmacokinetics of deuteratedanalogues in plasma and brain, with different routes of administration, as well as with differentformulations of the investigated ligand. While the strategy of deuteration and fluorinationincreased metabolic stability, the pharmacokinetic influence on plasma, brain, liver and kidneyexposure was dramatically different. Namely, the fluorinated analogues showed significantretention in the excretory organs (liver and kidney). Also, they exhibited a slightly increasedcytotoxic effect on liver and kidney cell lines in vitro. Efficacy and functional selectivity for theα6+β3- interface (PQ site) of α6-GABAARs was reduced for the fluorinated analogs in comparisonto the deuterated ligands. All these facts make them less suitable for further research. Thus, thedeuteration strategy proved superior to fluorination of these PQs in terms of maintaining α6-GABAAR selectivity while enhancing the metabolic stability and bioavailability. These α6-GABAAR ligands were devoid of observable detrimental effects...",
publisher = "Универзитет у Београду, Фармацеутски факултет",
journal = "Универзитет у Београду",
title = "Farmakološka karakterizacija uticaja deuteracije izabranih pirazolohinolinona kao modulatora GABAA receptora",
url = "https://hdl.handle.net/21.15107/rcub_nardus_21487"
}

Divović-Matović, B.. (2023). Farmakološka karakterizacija uticaja deuteracije izabranih pirazolohinolinona kao modulatora GABAA receptora. in Универзитет у Београду
Универзитет у Београду, Фармацеутски факултет..
https://hdl.handle.net/21.15107/rcub_nardus_21487

Divović-Matović B. Farmakološka karakterizacija uticaja deuteracije izabranih pirazolohinolinona kao modulatora GABAA receptora. in Универзитет у Београду. 2023;.
https://hdl.handle.net/21.15107/rcub_nardus_21487 .

Divović-Matović, Branka, "Farmakološka karakterizacija uticaja deuteracije izabranih pirazolohinolinona kao modulatora GABAA receptora" in Универзитет у Београду (2023),
https://hdl.handle.net/21.15107/rcub_nardus_21487 .

TY  - JOUR
AU  - Mian, Md Yeunus
AU  - Divović, Branka
AU  - Sharmin, Dishary
AU  - Pandey, Kamal P.
AU  - Golani, Lalit K.
AU  - Tiruveedhula, V. V. N. Phani Babu
AU  - Cerne, Rok
AU  - Smith, Jodi L.
AU  - Ping, Xingjie
AU  - Jin, Xiaoming
AU  - Imler, Gregory H.
AU  - Deschamps, Jeffrey R.
AU  - Lippa, Arnold
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Rowlett, James
AU  - Witkin, Jeffrey M.
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4363
AB  - Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABAA receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1H NMR and 13C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation.
PB  - ACS Publications
T2  - ACS Omega
T1  - Hydrochloride Salt of the GABAkine KRM-II-81
VL  - 7
IS  - 31
SP  - 27550
EP  - 27559
DO  - 10.1021/acsomega.2c03029
ER  - 

@article{
author = "Mian, Md Yeunus and Divović, Branka and Sharmin, Dishary and Pandey, Kamal P. and Golani, Lalit K. and Tiruveedhula, V. V. N. Phani Babu and Cerne, Rok and Smith, Jodi L. and Ping, Xingjie and Jin, Xiaoming and Imler, Gregory H. and Deschamps, Jeffrey R. and Lippa, Arnold and Cook, James M. and Savić, Miroslav and Rowlett, James and Witkin, Jeffrey M.",
year = "2022",
abstract = "Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABAA receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1H NMR and 13C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation.",
publisher = "ACS Publications",
journal = "ACS Omega",
title = "Hydrochloride Salt of the GABAkine KRM-II-81",
volume = "7",
number = "31",
pages = "27550-27559",
doi = "10.1021/acsomega.2c03029"
}

Mian, M. Y., Divović, B., Sharmin, D., Pandey, K. P., Golani, L. K., Tiruveedhula, V. V. N. P. B., Cerne, R., Smith, J. L., Ping, X., Jin, X., Imler, G. H., Deschamps, J. R., Lippa, A., Cook, J. M., Savić, M., Rowlett, J.,& Witkin, J. M.. (2022). Hydrochloride Salt of the GABAkine KRM-II-81. in ACS Omega
ACS Publications., 7(31), 27550-27559.
https://doi.org/10.1021/acsomega.2c03029

Mian MY, Divović B, Sharmin D, Pandey KP, Golani LK, Tiruveedhula VVNPB, Cerne R, Smith JL, Ping X, Jin X, Imler GH, Deschamps JR, Lippa A, Cook JM, Savić M, Rowlett J, Witkin JM. Hydrochloride Salt of the GABAkine KRM-II-81. in ACS Omega. 2022;7(31):27550-27559.
doi:10.1021/acsomega.2c03029 .

Mian, Md Yeunus, Divović, Branka, Sharmin, Dishary, Pandey, Kamal P., Golani, Lalit K., Tiruveedhula, V. V. N. Phani Babu, Cerne, Rok, Smith, Jodi L., Ping, Xingjie, Jin, Xiaoming, Imler, Gregory H., Deschamps, Jeffrey R., Lippa, Arnold, Cook, James M., Savić, Miroslav, Rowlett, James, Witkin, Jeffrey M., "Hydrochloride Salt of the GABAkine KRM-II-81" in ACS Omega, 7, no. 31 (2022):27550-27559,
https://doi.org/10.1021/acsomega.2c03029 . .

TY  - JOUR
AU  - Golani, Lalit
AU  - Divović, Branka
AU  - Sharmin, Dishary
AU  - Pandey, Kamal
AU  - Mian, Md Yeunus
AU  - Cerne, Rok
AU  - Zahn, Nicolas
AU  - Meyer, Michelle
AU  - Tiruveedhula, Veera
AU  - Smith, Jodi
AU  - Ping, Xingjie
AU  - Jin, Xiaoming
AU  - Lippa, Arnold
AU  - Schkeryantz, Jeffrey
AU  - Arnold, Leggy
AU  - Cook, James
AU  - Savić, Miroslav
AU  - Witkin, Jeffrey
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4108
AB  - The imidazodiazepine, (5‐(8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo [f]imidazole[1,5‐α] [1,4]diazepin‐3‐yl) oxazole or KRM‐II‐81) is a new α2/3‐selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half‐life of KRM‐II‐81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM‐II‐81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5‐KRM‐II‐ 81) that could be evaluated as a potentially longer‐acting analog. In contrast to computer predictions, peak plasma concentrations of D5‐KRM‐II‐81 in rats were not significantly greater than those produced by KRM‐II‐81 after oral administra- tion. Furthermore, brain disposition of KRM‐II‐81 was higher than that of D5‐KRM‐ II‐81. The half‐life of the two compounds in either plasma or brain did not statis- tically differ from one another but the tmax for D5‐KRM‐II‐81 occurred slightly earlier than for KRM‐II‐81. Non‐metabolic considerations might be relevant to the lack of increases in exposure by D5‐KRM‐II‐81. Alternative sites of metabolism on KRM‐II‐81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5‐KRM‐II‐81, like KRM‐II‐81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5‐KRM‐II‐81.
PB  - John Wiley and Sons Ltd
T2  - Biopharmaceutics and Drug Disposition
T1  - Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81
VL  - 43
IS  - 2
SP  - 66
EP  - 75
DO  - 10.1002/bdd.2313
ER  - 

@article{
author = "Golani, Lalit and Divović, Branka and Sharmin, Dishary and Pandey, Kamal and Mian, Md Yeunus and Cerne, Rok and Zahn, Nicolas and Meyer, Michelle and Tiruveedhula, Veera and Smith, Jodi and Ping, Xingjie and Jin, Xiaoming and Lippa, Arnold and Schkeryantz, Jeffrey and Arnold, Leggy and Cook, James and Savić, Miroslav and Witkin, Jeffrey",
year = "2022",
abstract = "The imidazodiazepine, (5‐(8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo [f]imidazole[1,5‐α] [1,4]diazepin‐3‐yl) oxazole or KRM‐II‐81) is a new α2/3‐selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half‐life of KRM‐II‐81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM‐II‐81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5‐KRM‐II‐ 81) that could be evaluated as a potentially longer‐acting analog. In contrast to computer predictions, peak plasma concentrations of D5‐KRM‐II‐81 in rats were not significantly greater than those produced by KRM‐II‐81 after oral administra- tion. Furthermore, brain disposition of KRM‐II‐81 was higher than that of D5‐KRM‐ II‐81. The half‐life of the two compounds in either plasma or brain did not statis- tically differ from one another but the tmax for D5‐KRM‐II‐81 occurred slightly earlier than for KRM‐II‐81. Non‐metabolic considerations might be relevant to the lack of increases in exposure by D5‐KRM‐II‐81. Alternative sites of metabolism on KRM‐II‐81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5‐KRM‐II‐81, like KRM‐II‐81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5‐KRM‐II‐81.",
publisher = "John Wiley and Sons Ltd",
journal = "Biopharmaceutics and Drug Disposition",
title = "Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81",
volume = "43",
number = "2",
pages = "66-75",
doi = "10.1002/bdd.2313"
}

Golani, L., Divović, B., Sharmin, D., Pandey, K., Mian, M. Y., Cerne, R., Zahn, N., Meyer, M., Tiruveedhula, V., Smith, J., Ping, X., Jin, X., Lippa, A., Schkeryantz, J., Arnold, L., Cook, J., Savić, M.,& Witkin, J.. (2022). Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81. in Biopharmaceutics and Drug Disposition
John Wiley and Sons Ltd., 43(2), 66-75.
https://doi.org/10.1002/bdd.2313

Golani L, Divović B, Sharmin D, Pandey K, Mian MY, Cerne R, Zahn N, Meyer M, Tiruveedhula V, Smith J, Ping X, Jin X, Lippa A, Schkeryantz J, Arnold L, Cook J, Savić M, Witkin J. Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81. in Biopharmaceutics and Drug Disposition. 2022;43(2):66-75.
doi:10.1002/bdd.2313 .

Golani, Lalit, Divović, Branka, Sharmin, Dishary, Pandey, Kamal, Mian, Md Yeunus, Cerne, Rok, Zahn, Nicolas, Meyer, Michelle, Tiruveedhula, Veera, Smith, Jodi, Ping, Xingjie, Jin, Xiaoming, Lippa, Arnold, Schkeryantz, Jeffrey, Arnold, Leggy, Cook, James, Savić, Miroslav, Witkin, Jeffrey, "Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81" in Biopharmaceutics and Drug Disposition, 43, no. 2 (2022):66-75,
https://doi.org/10.1002/bdd.2313 . .

TY  - JOUR
AU  - Divović-Matović, Branka
AU  - Knutson, Dan
AU  - Mitrović, Jelena
AU  - Stevanović, Vladimir
AU  - Stanojević, Boban
AU  - Savić, Snežana
AU  - Cook, James
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4289
AB  - Several pyrazoloquinolinone (PQ) ligands were recently discovered as func-tionally selective positive modulators at the PQ site ofα6-containing GABAAreceptors. PQs are also neutral modulators at the benzodiazepine site. Weassessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of maleSprague–Dawley rats. An excellent behavioural safety profile of all tested PQswas demonstrated in the spontaneous locomotor activity, rotarod, loss of right-ing reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029and its analogues prevented the ataxic effects of the benzodiazepine, asassessed in the rotarod test and during monitoring of rat locomotor activityafter awakening from the loss of righting reflex. Published electrophysiologicalprofiles of PQ ligands imply that positive modulation elicited atα6-GABAAreceptors that contain theγ2 andδsubunit, rather than their neutral modula-tory action at the benzodiazepine site, may prevent the ataxic action of diaze-pam. Thus, PZ-II-029 and its deuterated analogues are not prone to untowardinteractions with benzodiazepines and may indeed completely abolish theirataxic action, seen at therapeutic, and especially toxic concentrations.
PB  - John Wiley and Sons Inc
T2  - Basic and Clinical Pharmacology and Toxicology
T1  - Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature
VL  - 131
IS  - 6
SP  - 514
EP  - 524
DO  - 10.1111/bcpt.13801
ER  - 

@article{
author = "Divović-Matović, Branka and Knutson, Dan and Mitrović, Jelena and Stevanović, Vladimir and Stanojević, Boban and Savić, Snežana and Cook, James and Savić, Miroslav",
year = "2022",
abstract = "Several pyrazoloquinolinone (PQ) ligands were recently discovered as func-tionally selective positive modulators at the PQ site ofα6-containing GABAAreceptors. PQs are also neutral modulators at the benzodiazepine site. Weassessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of maleSprague–Dawley rats. An excellent behavioural safety profile of all tested PQswas demonstrated in the spontaneous locomotor activity, rotarod, loss of right-ing reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029and its analogues prevented the ataxic effects of the benzodiazepine, asassessed in the rotarod test and during monitoring of rat locomotor activityafter awakening from the loss of righting reflex. Published electrophysiologicalprofiles of PQ ligands imply that positive modulation elicited atα6-GABAAreceptors that contain theγ2 andδsubunit, rather than their neutral modula-tory action at the benzodiazepine site, may prevent the ataxic action of diaze-pam. Thus, PZ-II-029 and its deuterated analogues are not prone to untowardinteractions with benzodiazepines and may indeed completely abolish theirataxic action, seen at therapeutic, and especially toxic concentrations.",
publisher = "John Wiley and Sons Inc",
journal = "Basic and Clinical Pharmacology and Toxicology",
title = "Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature",
volume = "131",
number = "6",
pages = "514-524",
doi = "10.1111/bcpt.13801"
}

Divović-Matović, B., Knutson, D., Mitrović, J., Stevanović, V., Stanojević, B., Savić, S., Cook, J.,& Savić, M.. (2022). Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature. in Basic and Clinical Pharmacology and Toxicology
John Wiley and Sons Inc., 131(6), 514-524.
https://doi.org/10.1111/bcpt.13801

Divović-Matović B, Knutson D, Mitrović J, Stevanović V, Stanojević B, Savić S, Cook J, Savić M. Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature. in Basic and Clinical Pharmacology and Toxicology. 2022;131(6):514-524.
doi:10.1111/bcpt.13801 .

Divović-Matović, Branka, Knutson, Dan, Mitrović, Jelena, Stevanović, Vladimir, Stanojević, Boban, Savić, Snežana, Cook, James, Savić, Miroslav, "Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABAA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature" in Basic and Clinical Pharmacology and Toxicology, 131, no. 6 (2022):514-524,
https://doi.org/10.1111/bcpt.13801 . .

TY  - JOUR
AU  - Mitrović, Jelena
AU  - Divović-Matović, Branka
AU  - Knutson, Daniel
AU  - Đoković, Jelena
AU  - Kremenović, Aleksandar
AU  - Dobričić, Vladimir
AU  - Ranđelović, Danijela
AU  - Pantelić, Ivana
AU  - Cook, James
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3934
AB  - Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.
PB  - MDPI AG
T2  - Pharmaceutics
T1  - Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach
VL  - 13
IS  - 8
DO  - 10.3390/pharmaceutics13081188
ER  - 

@article{
author = "Mitrović, Jelena and Divović-Matović, Branka and Knutson, Daniel and Đoković, Jelena and Kremenović, Aleksandar and Dobričić, Vladimir and Ranđelović, Danijela and Pantelić, Ivana and Cook, James and Savić, Miroslav and Savić, Snežana",
year = "2021",
abstract = "Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.",
publisher = "MDPI AG",
journal = "Pharmaceutics",
title = "Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach",
volume = "13",
number = "8",
doi = "10.3390/pharmaceutics13081188"
}

Mitrović, J., Divović-Matović, B., Knutson, D., Đoković, J., Kremenović, A., Dobričić, V., Ranđelović, D., Pantelić, I., Cook, J., Savić, M.,& Savić, S.. (2021). Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach. in Pharmaceutics
MDPI AG., 13(8).
https://doi.org/10.3390/pharmaceutics13081188

Mitrović J, Divović-Matović B, Knutson D, Đoković J, Kremenović A, Dobričić V, Ranđelović D, Pantelić I, Cook J, Savić M, Savić S. Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach. in Pharmaceutics. 2021;13(8).
doi:10.3390/pharmaceutics13081188 .

Mitrović, Jelena, Divović-Matović, Branka, Knutson, Daniel, Đoković, Jelena, Kremenović, Aleksandar, Dobričić, Vladimir, Ranđelović, Danijela, Pantelić, Ivana, Cook, James, Savić, Miroslav, Savić, Snežana, "Overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk-i-60-3 by nanonization: A knowledge-based approach" in Pharmaceutics, 13, no. 8 (2021),
https://doi.org/10.3390/pharmaceutics13081188 . .

TY  - JOUR
AU  - Mitrović, Jelena
AU  - Divović, Branka
AU  - Knutson, Daniel E.
AU  - Đoković, Jelena
AU  - Vulić, Predrag
AU  - Ranđelović, Danijela
AU  - Dobričić, Vladimir
AU  - Čalija, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3640
AB  - DK-I-56–1 (7‑methoxy‑2-(4‑methoxy‑d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), a recently developed deuterated pyrazoloquinolinone, has been recognized as a lead candidate for treatment of various neuropsychiatric disorders. During preclinical investigation of poorly water-soluble compounds such as DK-I-56–1, the application of nanotechnology could be advantageous due to improved safety and possibly increased bioavailability of nanosized formulation. DK-I-56–1 nanosuspensions stabilized by polysorbate 80, alone or in combination with poloxamers 188 i.e. 407 or d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared using a small-scale media milling device. With particle size 208.7–250.6 nm and polydispersity index <0.250, selected nanodiseprsions were stable for three weeks. Pharmacokinetic and biodistribution studies following intraperitoneal administration of three types of formulation in mice indicated high plasma DK-I-56–1 levels after solution (10,228.6 ± 1037.2 ngh/ml) and nanosuspension (6770.4 ± 770.7 ngh/ml) but not suspension administration (966.0 ± 58.1 ngh/ml). However, distribution of DK-I-56–1 after solution was heavily influenced by its composition, and brain availability of nanosuspension was superior to that of solution formulation. In spontaneous locomotor activity test, the expected hyperlocomotor effect was observed after nanosuspension administration, without compromising impact of the vehicle/excipients used. Therefore, nanonization of drug compound assembled with proper selection of stabilizers may seemingly contribute further thorough testing of DK-I-56–1 preclinical efficacy.
PB  - Elsevier B.V.
T2  - European Journal of Pharmaceutical Sciences
T1  - Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance
VL  - 152
DO  - 10.1016/j.ejps.2020.105432
ER  - 

@article{
author = "Mitrović, Jelena and Divović, Branka and Knutson, Daniel E. and Đoković, Jelena and Vulić, Predrag and Ranđelović, Danijela and Dobričić, Vladimir and Čalija, Bojan and Cook, James M. and Savić, Miroslav and Savić, Snežana",
year = "2020",
abstract = "DK-I-56–1 (7‑methoxy‑2-(4‑methoxy‑d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), a recently developed deuterated pyrazoloquinolinone, has been recognized as a lead candidate for treatment of various neuropsychiatric disorders. During preclinical investigation of poorly water-soluble compounds such as DK-I-56–1, the application of nanotechnology could be advantageous due to improved safety and possibly increased bioavailability of nanosized formulation. DK-I-56–1 nanosuspensions stabilized by polysorbate 80, alone or in combination with poloxamers 188 i.e. 407 or d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared using a small-scale media milling device. With particle size 208.7–250.6 nm and polydispersity index <0.250, selected nanodiseprsions were stable for three weeks. Pharmacokinetic and biodistribution studies following intraperitoneal administration of three types of formulation in mice indicated high plasma DK-I-56–1 levels after solution (10,228.6 ± 1037.2 ngh/ml) and nanosuspension (6770.4 ± 770.7 ngh/ml) but not suspension administration (966.0 ± 58.1 ngh/ml). However, distribution of DK-I-56–1 after solution was heavily influenced by its composition, and brain availability of nanosuspension was superior to that of solution formulation. In spontaneous locomotor activity test, the expected hyperlocomotor effect was observed after nanosuspension administration, without compromising impact of the vehicle/excipients used. Therefore, nanonization of drug compound assembled with proper selection of stabilizers may seemingly contribute further thorough testing of DK-I-56–1 preclinical efficacy.",
publisher = "Elsevier B.V.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance",
volume = "152",
doi = "10.1016/j.ejps.2020.105432"
}

Mitrović, J., Divović, B., Knutson, D. E., Đoković, J., Vulić, P., Ranđelović, D., Dobričić, V., Čalija, B., Cook, J. M., Savić, M.,& Savić, S.. (2020). Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance. in European Journal of Pharmaceutical Sciences
Elsevier B.V.., 152.
https://doi.org/10.1016/j.ejps.2020.105432

Mitrović J, Divović B, Knutson DE, Đoković J, Vulić P, Ranđelović D, Dobričić V, Čalija B, Cook JM, Savić M, Savić S. Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance. in European Journal of Pharmaceutical Sciences. 2020;152.
doi:10.1016/j.ejps.2020.105432 .

Mitrović, Jelena, Divović, Branka, Knutson, Daniel E., Đoković, Jelena, Vulić, Predrag, Ranđelović, Danijela, Dobričić, Vladimir, Čalija, Bojan, Cook, James M., Savić, Miroslav, Savić, Snežana, "Nanocrystal dispersion of DK-I-56–1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance" in European Journal of Pharmaceutical Sciences, 152 (2020),
https://doi.org/10.1016/j.ejps.2020.105432 . .

TY  - CONF
AU  - Mitrović, Jelena
AU  - Divović, Branka
AU  - Dobričić, Vladimir
AU  - Čalija, Bojan
AU  - Vulić, Jelena P.
AU  - Knutson, Daniel E.
AU  - Cook, James M.
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5542
AB  - Deuterated pyrazoloquinolinones, GABAn receptor ligands, are being investigated for neuropsychiatric disorders treatment. Among others, DK-l-56-1 (7-Methoxy-2-(4-methoxy-d3- p h e n yl ) - 2, 5 -d i h yd ro - 3 H - py r azolo -14,3 -clq u i n o I i n - 3-one) was chosen as the lead component [1]. Because of its low solubility in water (6.27 t0.74 pg/ml) nanosuspension formulation for prospective parenteral administration was carried out [2]. ...
C3  - 10th International Congress Nanotechnology in Medicine & Biology, 15 - 17. April 2019, Graz / Austria
T1  - Nanonization of new patent protected substances - carrier selection for preclinical research: physicochemical and in vivo behavioral characterization
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5542
ER  - 

@conference{
author = "Mitrović, Jelena and Divović, Branka and Dobričić, Vladimir and Čalija, Bojan and Vulić, Jelena P. and Knutson, Daniel E. and Cook, James M. and Savić, Miroslav and Savić, Snežana",
year = "2019",
abstract = "Deuterated pyrazoloquinolinones, GABAn receptor ligands, are being investigated for neuropsychiatric disorders treatment. Among others, DK-l-56-1 (7-Methoxy-2-(4-methoxy-d3- p h e n yl ) - 2, 5 -d i h yd ro - 3 H - py r azolo -14,3 -clq u i n o I i n - 3-one) was chosen as the lead component [1]. Because of its low solubility in water (6.27 t0.74 pg/ml) nanosuspension formulation for prospective parenteral administration was carried out [2]. ...",
journal = "10th International Congress Nanotechnology in Medicine & Biology, 15 - 17. April 2019, Graz / Austria",
title = "Nanonization of new patent protected substances - carrier selection for preclinical research: physicochemical and in vivo behavioral characterization",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5542"
}

Mitrović, J., Divović, B., Dobričić, V., Čalija, B., Vulić, J. P., Knutson, D. E., Cook, J. M., Savić, M.,& Savić, S.. (2019). Nanonization of new patent protected substances - carrier selection for preclinical research: physicochemical and in vivo behavioral characterization. in 10th International Congress Nanotechnology in Medicine & Biology, 15 - 17. April 2019, Graz / Austria.
https://hdl.handle.net/21.15107/rcub_farfar_5542

Mitrović J, Divović B, Dobričić V, Čalija B, Vulić JP, Knutson DE, Cook JM, Savić M, Savić S. Nanonization of new patent protected substances - carrier selection for preclinical research: physicochemical and in vivo behavioral characterization. in 10th International Congress Nanotechnology in Medicine & Biology, 15 - 17. April 2019, Graz / Austria. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_5542 .

Mitrović, Jelena, Divović, Branka, Dobričić, Vladimir, Čalija, Bojan, Vulić, Jelena P., Knutson, Daniel E., Cook, James M., Savić, Miroslav, Savić, Snežana, "Nanonization of new patent protected substances - carrier selection for preclinical research: physicochemical and in vivo behavioral characterization" in 10th International Congress Nanotechnology in Medicine & Biology, 15 - 17. April 2019, Graz / Austria (2019),
https://hdl.handle.net/21.15107/rcub_farfar_5542 .

TY  - JOUR
AU  - Vasović, Dina
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Knutson, Daniel
AU  - Steudle, Friederike
AU  - Scholze, Petra
AU  - Obradović, Aleksandar
AU  - Fabjan, Jure
AU  - Brković, Božidar
AU  - Sieghart, Werner
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3315
AB  - gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.
PB  - Wiley, Hoboken
T2  - European Journal of Pain
T1  - Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors
VL  - 23
IS  - 5
SP  - 973
EP  - 984
DO  - 10.1002/ejp.1365
ER  - 

@article{
author = "Vasović, Dina and Divović, Branka and Treven, Marco and Knutson, Daniel and Steudle, Friederike and Scholze, Petra and Obradović, Aleksandar and Fabjan, Jure and Brković, Božidar and Sieghart, Werner and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2019",
abstract = "gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain.",
publisher = "Wiley, Hoboken",
journal = "European Journal of Pain",
title = "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors",
volume = "23",
number = "5",
pages = "973-984",
doi = "10.1002/ejp.1365"
}

Vasović, D., Divović, B., Treven, M., Knutson, D., Steudle, F., Scholze, P., Obradović, A., Fabjan, J., Brković, B., Sieghart, W., Ernst, M., Cook, J. M.,& Savić, M.. (2019). Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors. in European Journal of Pain
Wiley, Hoboken., 23(5), 973-984.
https://doi.org/10.1002/ejp.1365

Vasović D, Divović B, Treven M, Knutson D, Steudle F, Scholze P, Obradović A, Fabjan J, Brković B, Sieghart W, Ernst M, Cook JM, Savić M. Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors. in European Journal of Pain. 2019;23(5):973-984.
doi:10.1002/ejp.1365 .

Vasović, Dina, Divović, Branka, Treven, Marco, Knutson, Daniel, Steudle, Friederike, Scholze, Petra, Obradović, Aleksandar, Fabjan, Jure, Brković, Božidar, Sieghart, Werner, Ernst, Margot, Cook, James M., Savić, Miroslav, "Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors" in European Journal of Pain, 23, no. 5 (2019):973-984,
https://doi.org/10.1002/ejp.1365 . .

TY  - JOUR
AU  - Knutson, Daniel
AU  - Kodali, Revathi
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Stephen, Michael
AU  - Zahn, Nicolas
AU  - Dobričić, Vladimir
AU  - Huber, Alec
AU  - Meirelles, Matheus
AU  - Verma, Ranjit
AU  - Wimmer, Laurin
AU  - Witzigmann, Christopher
AU  - Arnold, Leggy
AU  - Chiou, Lih-Chu
AU  - Ernst, Margot
AU  - Mihovilović, Marko D.
AU  - Savić, Miroslav
AU  - Sieghart, Werner
AU  - Cook, James M.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3147
AB  - Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.
PB  - Amer Chemical Soc, Washington
T2  - Journal of Medicinal Chemistry
T1  - Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
VL  - 61
IS  - 6
SP  - 2422
EP  - 2446
DO  - 10.1021/acs.jmedchem.7b01664
ER  - 

@article{
author = "Knutson, Daniel and Kodali, Revathi and Divović, Branka and Treven, Marco and Stephen, Michael and Zahn, Nicolas and Dobričić, Vladimir and Huber, Alec and Meirelles, Matheus and Verma, Ranjit and Wimmer, Laurin and Witzigmann, Christopher and Arnold, Leggy and Chiou, Lih-Chu and Ernst, Margot and Mihovilović, Marko D. and Savić, Miroslav and Sieghart, Werner and Cook, James M.",
year = "2018",
abstract = "Recent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.",
publisher = "Amer Chemical Soc, Washington",
journal = "Journal of Medicinal Chemistry",
title = "Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability",
volume = "61",
number = "6",
pages = "2422-2446",
doi = "10.1021/acs.jmedchem.7b01664"
}

Knutson, D., Kodali, R., Divović, B., Treven, M., Stephen, M., Zahn, N., Dobričić, V., Huber, A., Meirelles, M., Verma, R., Wimmer, L., Witzigmann, C., Arnold, L., Chiou, L., Ernst, M., Mihovilović, M. D., Savić, M., Sieghart, W.,& Cook, J. M.. (2018). Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. in Journal of Medicinal Chemistry
Amer Chemical Soc, Washington., 61(6), 2422-2446.
https://doi.org/10.1021/acs.jmedchem.7b01664

Knutson D, Kodali R, Divović B, Treven M, Stephen M, Zahn N, Dobričić V, Huber A, Meirelles M, Verma R, Wimmer L, Witzigmann C, Arnold L, Chiou L, Ernst M, Mihovilović MD, Savić M, Sieghart W, Cook JM. Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. in Journal of Medicinal Chemistry. 2018;61(6):2422-2446.
doi:10.1021/acs.jmedchem.7b01664 .

Knutson, Daniel, Kodali, Revathi, Divović, Branka, Treven, Marco, Stephen, Michael, Zahn, Nicolas, Dobričić, Vladimir, Huber, Alec, Meirelles, Matheus, Verma, Ranjit, Wimmer, Laurin, Witzigmann, Christopher, Arnold, Leggy, Chiou, Lih-Chu, Ernst, Margot, Mihovilović, Marko D., Savić, Miroslav, Sieghart, Werner, Cook, James M., "Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability" in Journal of Medicinal Chemistry, 61, no. 6 (2018):2422-2446,
https://doi.org/10.1021/acs.jmedchem.7b01664 . .

TY  - CONF
AU  - Knutson, Daniel
AU  - Vasović, Dina
AU  - Divović, Branka
AU  - Treven, Marco
AU  - Steudle, Friederike
AU  - Scholze, Petra
AU  - Brković, Božidar
AU  - Sieghart, Werner
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3052
PB  - Amer Chemical Soc, Washington
C3  - Abstracts of Papers of the American Chemical Society
T1  - Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands
VL  - 256
UR  - https://hdl.handle.net/21.15107/rcub_farfar_3052
ER  - 

@conference{
author = "Knutson, Daniel and Vasović, Dina and Divović, Branka and Treven, Marco and Steudle, Friederike and Scholze, Petra and Brković, Božidar and Sieghart, Werner and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2018",
publisher = "Amer Chemical Soc, Washington",
journal = "Abstracts of Papers of the American Chemical Society",
title = "Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands",
volume = "256",
url = "https://hdl.handle.net/21.15107/rcub_farfar_3052"
}

Knutson, D., Vasović, D., Divović, B., Treven, M., Steudle, F., Scholze, P., Brković, B., Sieghart, W., Ernst, M., Cook, J. M.,& Savić, M.. (2018). Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands. in Abstracts of Papers of the American Chemical Society
Amer Chemical Soc, Washington., 256.
https://hdl.handle.net/21.15107/rcub_farfar_3052

Knutson D, Vasović D, Divović B, Treven M, Steudle F, Scholze P, Brković B, Sieghart W, Ernst M, Cook JM, Savić M. Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands. in Abstracts of Papers of the American Chemical Society. 2018;256.
https://hdl.handle.net/21.15107/rcub_farfar_3052 .

Knutson, Daniel, Vasović, Dina, Divović, Branka, Treven, Marco, Steudle, Friederike, Scholze, Petra, Brković, Božidar, Sieghart, Werner, Ernst, Margot, Cook, James M., Savić, Miroslav, "Prevention of trigeminal neuropathic pain development in rats using novel deuterated GABAAR-alpha 6 subtype selective ligands" in Abstracts of Papers of the American Chemical Society, 256 (2018),
https://hdl.handle.net/21.15107/rcub_farfar_3052 .

TY  - JOUR
AU  - Đorđević, Sanela
AU  - Santrač, Anja
AU  - Cekić, Nebojša
AU  - Marković, Bojan
AU  - Divović, Branka
AU  - Ilić, Tanja
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2883
AB  - This work aimed to deepen the lately acquired knowledge about parenteral nanoemulsions as carriers for brain delivery of risperidone, a poorly water-soluble antipsychotic drug, through establishing the prospective relationship between their physicochemical, pharmacokinetic, biodistribution, and behavioral performances. For this purpose, two optimized risperidone-loaded nanoemulsions, stabilized by lecithin or lecithin/polysorbate 80 mixture, and costabilized by sodium oleate, were produced by high-pressure homogenization. The characterization revealed the favorable droplet size, narrow size distribution, high surface charge, with proven stability to autoclaving and long-term stability for at least one year at 25 +/- 2 degrees C. Pharmacokinetic and tissue distribution results demonstrated improved plasma, liver, and brain pharmacokinetic parameters, resulting in 1.2-1.5-fold increased relative bioavailability, 1.1-1.8-fold decreased liver distribution, and about 1.3-fold improved brain uptake of risperidone active moiety following intraperitoneal administration of nanoemulsions relative to solution in rats. In behavioral study, investigated nanoemulsions showed pronounced reduction in basal and, more pertinently, amphetamine-induced locomotor activity in rats, with an early onset of antipsychotic action, and this effect lasted at least 90 min after drug injection. Together, these findings corroborate the applicability of parenteral nanoemulsions as carriers for enhanced brain delivery of risperidone, further suggesting their promise in acute psychosis treatment or other emergency situations.
PB  - Elsevier Science BV, Amsterdam
T2  - International Journal of Pharmaceutics
T1  - Parenteral nanoemulsions of risperidone for enhanced brain delivery in acute psychosis: Physicochemical and in vivo performances
VL  - 533
IS  - 2
SP  - 421
EP  - 430
DO  - 10.1016/j.ijpharm.2017.05.051
ER  - 

@article{
author = "Đorđević, Sanela and Santrač, Anja and Cekić, Nebojša and Marković, Bojan and Divović, Branka and Ilić, Tanja and Savić, Miroslav and Savić, Snežana",
year = "2017",
abstract = "This work aimed to deepen the lately acquired knowledge about parenteral nanoemulsions as carriers for brain delivery of risperidone, a poorly water-soluble antipsychotic drug, through establishing the prospective relationship between their physicochemical, pharmacokinetic, biodistribution, and behavioral performances. For this purpose, two optimized risperidone-loaded nanoemulsions, stabilized by lecithin or lecithin/polysorbate 80 mixture, and costabilized by sodium oleate, were produced by high-pressure homogenization. The characterization revealed the favorable droplet size, narrow size distribution, high surface charge, with proven stability to autoclaving and long-term stability for at least one year at 25 +/- 2 degrees C. Pharmacokinetic and tissue distribution results demonstrated improved plasma, liver, and brain pharmacokinetic parameters, resulting in 1.2-1.5-fold increased relative bioavailability, 1.1-1.8-fold decreased liver distribution, and about 1.3-fold improved brain uptake of risperidone active moiety following intraperitoneal administration of nanoemulsions relative to solution in rats. In behavioral study, investigated nanoemulsions showed pronounced reduction in basal and, more pertinently, amphetamine-induced locomotor activity in rats, with an early onset of antipsychotic action, and this effect lasted at least 90 min after drug injection. Together, these findings corroborate the applicability of parenteral nanoemulsions as carriers for enhanced brain delivery of risperidone, further suggesting their promise in acute psychosis treatment or other emergency situations.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "International Journal of Pharmaceutics",
title = "Parenteral nanoemulsions of risperidone for enhanced brain delivery in acute psychosis: Physicochemical and in vivo performances",
volume = "533",
number = "2",
pages = "421-430",
doi = "10.1016/j.ijpharm.2017.05.051"
}

Đorđević, S., Santrač, A., Cekić, N., Marković, B., Divović, B., Ilić, T., Savić, M.,& Savić, S.. (2017). Parenteral nanoemulsions of risperidone for enhanced brain delivery in acute psychosis: Physicochemical and in vivo performances. in International Journal of Pharmaceutics
Elsevier Science BV, Amsterdam., 533(2), 421-430.
https://doi.org/10.1016/j.ijpharm.2017.05.051

Đorđević S, Santrač A, Cekić N, Marković B, Divović B, Ilić T, Savić M, Savić S. Parenteral nanoemulsions of risperidone for enhanced brain delivery in acute psychosis: Physicochemical and in vivo performances. in International Journal of Pharmaceutics. 2017;533(2):421-430.
doi:10.1016/j.ijpharm.2017.05.051 .

Đorđević, Sanela, Santrač, Anja, Cekić, Nebojša, Marković, Bojan, Divović, Branka, Ilić, Tanja, Savić, Miroslav, Savić, Snežana, "Parenteral nanoemulsions of risperidone for enhanced brain delivery in acute psychosis: Physicochemical and in vivo performances" in International Journal of Pharmaceutics, 533, no. 2 (2017):421-430,
https://doi.org/10.1016/j.ijpharm.2017.05.051 . .

TY  - JOUR
AU  - Timić-Stamenić, Tamara
AU  - Poe, Michael M.
AU  - Rehman, Sabah
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Scholze, Petra
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2631
AB  - We have synthesized and characterized MP-III-022 ((R)-8-ethynyl 6 (2 fluorophenyl)-N,4-dimethyl4H-benzo[f]imidazo[1,5-alpha][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy selective positive allosteric modulator of GABA(A) receptors containing the alpha 5 subunit (alpha 5GABA(A)Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 110 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of alpha 5 beta gamma 2 GABA(A) receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-alpha 5 GABA(A)Rs as well as the desired alpha 5GABA(A)Rs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of alpha 5GABA(A)Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of alpha 5GABA(A)Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.
PB  - Elsevier Science BV, Amsterdam
T2  - European Journal of Pharmacology
T1  - Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit
VL  - 791
SP  - 433
EP  - 443
DO  - 10.1016/j.ejphar.2016.09.016
ER  - 

@article{
author = "Timić-Stamenić, Tamara and Poe, Michael M. and Rehman, Sabah and Santrač, Anja and Divović, Branka and Scholze, Petra and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2016",
abstract = "We have synthesized and characterized MP-III-022 ((R)-8-ethynyl 6 (2 fluorophenyl)-N,4-dimethyl4H-benzo[f]imidazo[1,5-alpha][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy selective positive allosteric modulator of GABA(A) receptors containing the alpha 5 subunit (alpha 5GABA(A)Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 110 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of alpha 5 beta gamma 2 GABA(A) receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-alpha 5 GABA(A)Rs as well as the desired alpha 5GABA(A)Rs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of alpha 5GABA(A)Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of alpha 5GABA(A)Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Journal of Pharmacology",
title = "Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit",
volume = "791",
pages = "433-443",
doi = "10.1016/j.ejphar.2016.09.016"
}

Timić-Stamenić, T., Poe, M. M., Rehman, S., Santrač, A., Divović, B., Scholze, P., Ernst, M., Cook, J. M.,& Savić, M.. (2016). Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit. in European Journal of Pharmacology
Elsevier Science BV, Amsterdam., 791, 433-443.
https://doi.org/10.1016/j.ejphar.2016.09.016

Timić-Stamenić T, Poe MM, Rehman S, Santrač A, Divović B, Scholze P, Ernst M, Cook JM, Savić M. Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit. in European Journal of Pharmacology. 2016;791:433-443.
doi:10.1016/j.ejphar.2016.09.016 .

Timić-Stamenić, Tamara, Poe, Michael M., Rehman, Sabah, Santrač, Anja, Divović, Branka, Scholze, Petra, Ernst, Margot, Cook, James M., Savić, Miroslav, "Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit" in European Journal of Pharmacology, 791 (2016):433-443,
https://doi.org/10.1016/j.ejphar.2016.09.016 . .

TY  - JOUR
AU  - Batinić, Bojan
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Timić, Tamara
AU  - Stanković, Tamara
AU  - Obradović, Aleksandar
AU  - Joksimović, Srđan
AU  - Savić, Miroslav
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2558
AB  - Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100 mu g/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-alpha and IL-6 in dam blood withdrawn 2 h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5 mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.
PB  - Elsevier Science BV, Amsterdam
T2  - Behavioural Brain Research
T1  - Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring
VL  - 299
SP  - 72
EP  - 80
DO  - 10.1016/j.bbr.2015.11.025
ER  - 

@article{
author = "Batinić, Bojan and Santrač, Anja and Divović, Branka and Timić, Tamara and Stanković, Tamara and Obradović, Aleksandar and Joksimović, Srđan and Savić, Miroslav",
year = "2016",
abstract = "Numerous basic and epidemiological studies have connected prenatal maternal immune activation with the occurrence of schizophrenia and/or autism. Depending on subtle differences in protocols of the used animal model, a variety of behavioral abnormalities has been reported. This study investigated behavioral differences in Wistar rat offspring of both genders, exposed to the 100 mu g/kg per day dose of lipopolysaccharide (LPS) in late embryogenesis (embryonic days 15 and 16), while tested at their adolescent and young adult age (postnatal days 40 and 60, respectively). Immune activation was confirmed by detecting high levels of TNF-alpha and IL-6 in dam blood withdrawn 2 h after the first dose of LPS. The animals were assessed in three consecutive trials of locomotor activity (novelty exploration, response to i.p. saline injection and challenge with 0.5 mg/kg amphetamine), Morris water maze and social interaction tests. Overt behavioral dysfunction was perceived in adult rats only, and these changes were gender-distinctive. When compared with control rats, LPS females displayed baseline hypolocomotion and a decreased reactivity to amphetamine, while LPS males exhibited spatial learning (acquisition trials) and memory (probe trial) impairments. Prenatal treatment did not affect the time spent in social interaction. As maternal exposure to LPS in late gestation resulted in behavioral changes in offspring in early adulthood, it may model schizophrenia-like, but not autism-like endophenotypes. However, lack of a potentiated response to amphetamine testified that this model could not mimic positive symptoms, but rather certain traits of cognitive dysfunction and deficit symptoms, in males and females, respectively.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Behavioural Brain Research",
title = "Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring",
volume = "299",
pages = "72-80",
doi = "10.1016/j.bbr.2015.11.025"
}

Batinić, B., Santrač, A., Divović, B., Timić, T., Stanković, T., Obradović, A., Joksimović, S.,& Savić, M.. (2016). Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring. in Behavioural Brain Research
Elsevier Science BV, Amsterdam., 299, 72-80.
https://doi.org/10.1016/j.bbr.2015.11.025

Batinić B, Santrač A, Divović B, Timić T, Stanković T, Obradović A, Joksimović S, Savić M. Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring. in Behavioural Brain Research. 2016;299:72-80.
doi:10.1016/j.bbr.2015.11.025 .

Batinić, Bojan, Santrač, Anja, Divović, Branka, Timić, Tamara, Stanković, Tamara, Obradović, Aleksandar, Joksimović, Srđan, Savić, Miroslav, "Lipopolysaccharide exposure during late embryogenesis results in diminished locomotor activity and amphetamine response in females and spatial cognition impairment in males in adult, but not adolescent rat offspring" in Behavioural Brain Research, 299 (2016):72-80,
https://doi.org/10.1016/j.bbr.2015.11.025 . .

TY  - JOUR
AU  - Vidojević, Aleksandra
AU  - Živković, Aleksandra
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Savić, Miroslav
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2479
AB  - Introduction: Animal models enable the investigation of association between maternal inflammation during pregnancy and different neuropsychiatric disorders in offspring, which has been reported in epidemiological studies. Aim: Investigation of inflammation existence in female rats exposed to LPS during pregnancy and its influence on spatial memory impairment in offspring in Morris water maze. Material and methods: Pregnant Wistar females were exposed to LPS or saline (SAL) at gestational day 15 and 16 and their blood was taken for TNF-α concentration determination. Rats of both sexes (male - M, female - F) went through five-day memory acquisition and one-day memory retrieval test during two periods (35 - 39 postnatal day (P35-39) and P40; likewise P55-59 and P60). We analyzed memory acquisition (latency and path efficiency to platform finding and total distance travelled) and memory retrieval parameters (number of entries and path efficiency to first entry to the target zone). Results: We found higher TNF-α concentration present in LPS-treated dams. There were no significant differences for any of the parameters analyzed for P40 animals and P60 females. M/LPS/P60 rats had a significantly decreased path efficiency to platform finding, increased total distance travelled and a trend of increased latency to platform finding, compared to M/SAL/P60 in the memory acquisition test, and a significantly decreased path efficiency to first entry to the target zone in the memory retrieval test. Conclusion: Lipopolysaccharide (LPS) - induced maternal inflammation during pregnancy leads to spatial memory impairment in male rat offspring in early adulthood, a finding that can be a basis for animal modeling of neurodevelopmental disorders.
AB  - Uvod: Animalni modeli pružaju mogućnost ispitivanja veze između zapaljenja kod majki tokom trudnoće i različitih neuropsihijatrijskih poremećaja potomstva, pokazane u epidemiološkim studijama. Cilj rada: U ovom radu je ispitivano postojanje zapaljenja kod ženki pacova izloženih LPS-u tokom trudnoće i njegov uticaj na oštećenje prostorne memorije potomstva u Morisovom vodenom lavirintu. Materijal i metode: Gravidne ženke soja Wistar bile su izložene LPS-u ili fiziološkom rastvoru (SAL) 15. i 16. dana gestacije i uzimana im je krv radi određivanja koncentracije TNF-α. Mladunci oba pola (mužjaci - M, ženke - F) podvrgnuti su petodnevnom testu sticanja i jednodnevnom testu pozivanja memorije u dva postnatalna perioda (35 - 39. postnatalnog dana života (P35- 39) i P40, odnosno P55-59 i P60). Analizirani su parametri sticanja (latencija i efikasnost putanje do pronalaska platforme i ukupan pređeni put) i pozivanja prostorne memorije (broj ulazaka i efikasnost putanje do prvog ulaska u ciljnu zonu). Rezultati: Utvrđene su povišene koncentracije TNF-α kod majki tretiranih LPS-om. Kod P40 životinja nije bilo značajnih razlika u praćenim bihejvioralnim parametrima, kao ni kod P60 ženki. Pokazano je da su pacovi M/LPS/P60 imali statistički značajno manju efikasnost putanje do pronalaska platforme, veći ukupni pređeni put i trend povećanja latencije do pronalaska platforme u odnosu na M/SAL/P60 u testu sticanja memorije, kao i značajno manju efikasnost putanje do prvog ulaska u ciljnu zonu u testu pozivanja memorije. Zaključak: Lipopolisaharidom (LPS) izazvano zapaljenje kod ženki pacova tokom trudnoće utiče na oštećenje prostorne memorije kod potomstva muškog pola u ranom odraslom dobu, što bi moglo poslužiti za razvijanje animalnog modela neurorazvojnih oboljenja.
PB  - Univerzitet u Beogradu - Medicinski fakultet, Beograd
T2  - Medicinski podmladak
T1  - Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće
VL  - 66
IS  - 2
SP  - 37
EP  - 43
DO  - 10.5937/medpodm1502037V
ER  - 

@article{
author = "Vidojević, Aleksandra and Živković, Aleksandra and Santrač, Anja and Divović, Branka and Savić, Miroslav",
year = "2015",
abstract = "Introduction: Animal models enable the investigation of association between maternal inflammation during pregnancy and different neuropsychiatric disorders in offspring, which has been reported in epidemiological studies. Aim: Investigation of inflammation existence in female rats exposed to LPS during pregnancy and its influence on spatial memory impairment in offspring in Morris water maze. Material and methods: Pregnant Wistar females were exposed to LPS or saline (SAL) at gestational day 15 and 16 and their blood was taken for TNF-α concentration determination. Rats of both sexes (male - M, female - F) went through five-day memory acquisition and one-day memory retrieval test during two periods (35 - 39 postnatal day (P35-39) and P40; likewise P55-59 and P60). We analyzed memory acquisition (latency and path efficiency to platform finding and total distance travelled) and memory retrieval parameters (number of entries and path efficiency to first entry to the target zone). Results: We found higher TNF-α concentration present in LPS-treated dams. There were no significant differences for any of the parameters analyzed for P40 animals and P60 females. M/LPS/P60 rats had a significantly decreased path efficiency to platform finding, increased total distance travelled and a trend of increased latency to platform finding, compared to M/SAL/P60 in the memory acquisition test, and a significantly decreased path efficiency to first entry to the target zone in the memory retrieval test. Conclusion: Lipopolysaccharide (LPS) - induced maternal inflammation during pregnancy leads to spatial memory impairment in male rat offspring in early adulthood, a finding that can be a basis for animal modeling of neurodevelopmental disorders., Uvod: Animalni modeli pružaju mogućnost ispitivanja veze između zapaljenja kod majki tokom trudnoće i različitih neuropsihijatrijskih poremećaja potomstva, pokazane u epidemiološkim studijama. Cilj rada: U ovom radu je ispitivano postojanje zapaljenja kod ženki pacova izloženih LPS-u tokom trudnoće i njegov uticaj na oštećenje prostorne memorije potomstva u Morisovom vodenom lavirintu. Materijal i metode: Gravidne ženke soja Wistar bile su izložene LPS-u ili fiziološkom rastvoru (SAL) 15. i 16. dana gestacije i uzimana im je krv radi određivanja koncentracije TNF-α. Mladunci oba pola (mužjaci - M, ženke - F) podvrgnuti su petodnevnom testu sticanja i jednodnevnom testu pozivanja memorije u dva postnatalna perioda (35 - 39. postnatalnog dana života (P35- 39) i P40, odnosno P55-59 i P60). Analizirani su parametri sticanja (latencija i efikasnost putanje do pronalaska platforme i ukupan pređeni put) i pozivanja prostorne memorije (broj ulazaka i efikasnost putanje do prvog ulaska u ciljnu zonu). Rezultati: Utvrđene su povišene koncentracije TNF-α kod majki tretiranih LPS-om. Kod P40 životinja nije bilo značajnih razlika u praćenim bihejvioralnim parametrima, kao ni kod P60 ženki. Pokazano je da su pacovi M/LPS/P60 imali statistički značajno manju efikasnost putanje do pronalaska platforme, veći ukupni pređeni put i trend povećanja latencije do pronalaska platforme u odnosu na M/SAL/P60 u testu sticanja memorije, kao i značajno manju efikasnost putanje do prvog ulaska u ciljnu zonu u testu pozivanja memorije. Zaključak: Lipopolisaharidom (LPS) izazvano zapaljenje kod ženki pacova tokom trudnoće utiče na oštećenje prostorne memorije kod potomstva muškog pola u ranom odraslom dobu, što bi moglo poslužiti za razvijanje animalnog modela neurorazvojnih oboljenja.",
publisher = "Univerzitet u Beogradu - Medicinski fakultet, Beograd",
journal = "Medicinski podmladak",
title = "Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće",
volume = "66",
number = "2",
pages = "37-43",
doi = "10.5937/medpodm1502037V"
}

Vidojević, A., Živković, A., Santrač, A., Divović, B.,& Savić, M.. (2015). Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće. in Medicinski podmladak
Univerzitet u Beogradu - Medicinski fakultet, Beograd., 66(2), 37-43.
https://doi.org/10.5937/medpodm1502037V

Vidojević A, Živković A, Santrač A, Divović B, Savić M. Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće. in Medicinski podmladak. 2015;66(2):37-43.
doi:10.5937/medpodm1502037V .

Vidojević, Aleksandra, Živković, Aleksandra, Santrač, Anja, Divović, Branka, Savić, Miroslav, "Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće" in Medicinski podmladak, 66, no. 2 (2015):37-43,
https://doi.org/10.5937/medpodm1502037V . .

TY  - CONF
AU  - Timić-Stamenić, Tamara
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Poe, Michael M.
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2424
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion
VL  - 25
IS  - Supplement 1
SP  - S38
EP  - S39
DO  - 10.1016/S0924-977X(15)30007-9
ER  - 

@conference{
author = "Timić-Stamenić, Tamara and Santrač, Anja and Divović, Branka and Poe, Michael M. and Cook, James M. and Savić, Miroslav",
year = "2015",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion",
volume = "25",
number = "Supplement 1",
pages = "S38-S39",
doi = "10.1016/S0924-977X(15)30007-9"
}

Timić-Stamenić, T., Santrač, A., Divović, B., Poe, M. M., Cook, J. M.,& Savić, M.. (2015). Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 25(Supplement 1), S38-S39.
https://doi.org/10.1016/S0924-977X(15)30007-9

Timić-Stamenić T, Santrač A, Divović B, Poe MM, Cook JM, Savić M. Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion. in European Neuropsychopharmacology. 2015;25(Supplement 1):S38-S39.
doi:10.1016/S0924-977X(15)30007-9 .

Timić-Stamenić, Tamara, Santrač, Anja, Divović, Branka, Poe, Michael M., Cook, James M., Savić, Miroslav, "Effects of positive alpha5-selective
modulation of GABA A receptors on
amphetamine-induced hyperlocomotion" in European Neuropsychopharmacology, 25, no. Supplement 1 (2015):S38-S39,
https://doi.org/10.1016/S0924-977X(15)30007-9 . .

TY  - CONF
AU  - Timić-Stamenić, Tamara
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Poe, Michael M.
AU  - James, C. M.
AU  - Savić, Miroslav
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2305
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation
VL  - 25
SP  - S287
EP  - S288
DO  - 10.1016/S0924-977X(15)30342-4
ER  - 

@conference{
author = "Timić-Stamenić, Tamara and Santrač, Anja and Divović, Branka and Poe, Michael M. and James, C. M. and Savić, Miroslav",
year = "2015",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation",
volume = "25",
pages = "S287-S288",
doi = "10.1016/S0924-977X(15)30342-4"
}

Timić-Stamenić, T., Santrač, A., Divović, B., Poe, M. M., James, C. M.,& Savić, M.. (2015). Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 25, S287-S288.
https://doi.org/10.1016/S0924-977X(15)30342-4

Timić-Stamenić T, Santrač A, Divović B, Poe MM, James CM, Savić M. Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation. in European Neuropsychopharmacology. 2015;25:S287-S288.
doi:10.1016/S0924-977X(15)30342-4 .

Timić-Stamenić, Tamara, Santrač, Anja, Divović, Branka, Poe, Michael M., James, C. M., Savić, Miroslav, "Effects of positive α5-selective modulation of GABAA receptors on amphetamine-induced hyperactivation" in European Neuropsychopharmacology, 25 (2015):S287-S288,
https://doi.org/10.1016/S0924-977X(15)30342-4 . .