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  - 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  - 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  - 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 . .