TY  - JOUR
AU  - Gajić Bojić, Milica
AU  - Treven, Marco
AU  - Pandey, Kamal P
AU  - Tiruveedhula, Phani Babu V V N
AU  - Santrač, Anja
AU  - Đukanović, Đorđe
AU  - Vojinović, Nataša
AU  - Amidžić, Ljiljana
AU  - Škrbić, Ranko
AU  - Scholze, Petra
AU  - Ernst, Margot
AU  - Cook, James M
AU  - Savić, Miroslav
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5619
AB  - Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of “vascular” GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ 2 and α1-5 subunit proteins. To confirm the role of “vascular” GABAA receptors, we investigated the vascular effects of standard benzodiazepines, mida-zolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ 2 over other αxβ3γ 2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazo-lam, both of which at 100 μmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.
PB  - Canadian Science Publishing
T2  - Canadian  Journal of Physiology and  Pharmacology
T1  - Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta
VL  - 102
IS  - 3
SP  - 206
EP  - 217
DO  - 10.1139/cjpp-2023-0285
ER  - 

@article{
author = "Gajić Bojić, Milica and Treven, Marco and Pandey, Kamal P and Tiruveedhula, Phani Babu V V N and Santrač, Anja and Đukanović, Đorđe and Vojinović, Nataša and Amidžić, Ljiljana and Škrbić, Ranko and Scholze, Petra and Ernst, Margot and Cook, James M and Savić, Miroslav",
year = "2024",
abstract = "Hypotensive influences of benzodiazepines and other GABAA receptor ligands, recognized in clinical practice, seem to stem from the existence of “vascular” GABAA receptors in peripheral blood vessels, besides any mechanisms in the central and peripheral nervous systems. We aimed to further elucidate the vasodilatatory effects of ligands acting through GABAA receptors. Using immunohistochemistry, the rat aortic smooth muscle layer was found to express GABAA γ 2 and α1-5 subunit proteins. To confirm the role of “vascular” GABAA receptors, we investigated the vascular effects of standard benzodiazepines, mida-zolam, and flumazenil, as well as the novel compound MP-III-058. Using two-electrode voltage clamp electrophysiology and radioligand binding assays, MP-III-058 was found to have modest binding but substantial functional selectivity for α5β3γ 2 over other αxβ3γ 2 GABAA receptors. Tissue bath assays revealed comparable vasodilatory effects of MP-III-058 and midazo-lam, both of which at 100 μmol/L concentrations had efficacy similar to prazosin. Flumazenil exhibited weak vasoactivity per se, but significantly prevented the relaxant effects of midazolam and MP-III-058. These studies indicate the existence of functional GABAA receptors in the rat aorta, where ligands exert vasodilatory effects by positive modulation of the benzodiazepine binding site, suggesting the potential for further quest for leads with optimized pharmacokinetic properties as prospective adjuvant vasodilators.",
publisher = "Canadian Science Publishing",
journal = "Canadian  Journal of Physiology and  Pharmacology",
title = "Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta",
volume = "102",
number = "3",
pages = "206-217",
doi = "10.1139/cjpp-2023-0285"
}

Gajić Bojić, M., Treven, M., Pandey, K. P., Tiruveedhula, P. B. V. V. N., Santrač, A., Đukanović, Đ., Vojinović, N., Amidžić, L., Škrbić, R., Scholze, P., Ernst, M., Cook, J. M.,& Savić, M.. (2024). Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta. in Canadian  Journal of Physiology and  Pharmacology
Canadian Science Publishing., 102(3), 206-217.
https://doi.org/10.1139/cjpp-2023-0285

Gajić Bojić M, Treven M, Pandey KP, Tiruveedhula PBVVN, Santrač A, Đukanović Đ, Vojinović N, Amidžić L, Škrbić R, Scholze P, Ernst M, Cook JM, Savić M. Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta. in Canadian  Journal of Physiology and  Pharmacology. 2024;102(3):206-217.
doi:10.1139/cjpp-2023-0285 .

Gajić Bojić, Milica, Treven, Marco, Pandey, Kamal P, Tiruveedhula, Phani Babu V V N, Santrač, Anja, Đukanović, Đorđe, Vojinović, Nataša, Amidžić, Ljiljana, Škrbić, Ranko, Scholze, Petra, Ernst, Margot, Cook, James M, Savić, Miroslav, "Vascular effects of midazolam, flumazenil, and a novel imidazobenzodiazepine MP-III-058 on isolated rat aorta" in Canadian  Journal of Physiology and  Pharmacology, 102, no. 3 (2024):206-217,
https://doi.org/10.1139/cjpp-2023-0285 . .

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  - 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  - Batinić, Bojan
AU  - Stanković, Tamara
AU  - Stephen, Michael
AU  - Kodali, Revathi
AU  - Tiruveedhula, Veera V.
AU  - Li, Guanguan
AU  - Scholze, Petra
AU  - Marković, Bojan
AU  - Obradović, Aleksandar
AU  - Ernst, Margot
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3070
AB  - It is unclear whether GABA(A) receptors (GABA(A)Rs) that contain the alpha 3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for alpha 3 ss gamma 2 GABA(A) Rs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2 mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10 mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and ss CCt, the non-selective and alpha 1 ss gamma 2 GABA(A)R affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the alpha 1 gamma 2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the alpha 1 gamma 2 over other BDZ-sensitive sites, and at lower doses (1-2 mg/kg) was devoid of potentiation at alpha 1 ss gamma 2 GABA(A)Rs. The approximation approach revealed a modest selectivity of YT-III-31 for alpha 3 gamma 2- in comparison to alpha 2 gamma 2 and alpha 5 gamma 2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at alpha 3 ss gamma 2 GABA(A)Rs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research.
PB  - Elsevier Science BV, Amsterdam
T2  - European Neuropsychopharmacology
T1  - Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!
VL  - 28
IS  - 8
SP  - 903
EP  - 914
DO  - 10.1016/j.euroneuro.2018.05.014
ER  - 

@article{
author = "Batinić, Bojan and Stanković, Tamara and Stephen, Michael and Kodali, Revathi and Tiruveedhula, Veera V. and Li, Guanguan and Scholze, Petra and Marković, Bojan and Obradović, Aleksandar and Ernst, Margot and Cook, James M. and Savić, Miroslav",
year = "2018",
abstract = "It is unclear whether GABA(A) receptors (GABA(A)Rs) that contain the alpha 3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for alpha 3 ss gamma 2 GABA(A) Rs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2 mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10 mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and ss CCt, the non-selective and alpha 1 ss gamma 2 GABA(A)R affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the alpha 1 gamma 2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the alpha 1 gamma 2 over other BDZ-sensitive sites, and at lower doses (1-2 mg/kg) was devoid of potentiation at alpha 1 ss gamma 2 GABA(A)Rs. The approximation approach revealed a modest selectivity of YT-III-31 for alpha 3 gamma 2- in comparison to alpha 2 gamma 2 and alpha 5 gamma 2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at alpha 3 ss gamma 2 GABA(A)Rs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!",
volume = "28",
number = "8",
pages = "903-914",
doi = "10.1016/j.euroneuro.2018.05.014"
}

Batinić, B., Stanković, T., Stephen, M., Kodali, R., Tiruveedhula, V. V., Li, G., Scholze, P., Marković, B., Obradović, A., Ernst, M., Cook, J. M.,& Savić, M.. (2018). Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 28(8), 903-914.
https://doi.org/10.1016/j.euroneuro.2018.05.014

Batinić B, Stanković T, Stephen M, Kodali R, Tiruveedhula VV, Li G, Scholze P, Marković B, Obradović A, Ernst M, Cook JM, Savić M. Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!. in European Neuropsychopharmacology. 2018;28(8):903-914.
doi:10.1016/j.euroneuro.2018.05.014 .

Batinić, Bojan, Stanković, Tamara, Stephen, Michael, Kodali, Revathi, Tiruveedhula, Veera V., Li, Guanguan, Scholze, Petra, Marković, Bojan, Obradović, Aleksandar, Ernst, Margot, Cook, James M., Savić, Miroslav, "Attaining in vivo selectivity of positive modulation of alpha 3 ss gamma 2 GABA(A) receptors in rats: A hard task!" in European Neuropsychopharmacology, 28, no. 8 (2018):903-914,
https://doi.org/10.1016/j.euroneuro.2018.05.014 . .

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  - 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 . .