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  - Bernardo, Ashley
AU  - Lee, Philip
AU  - Marcotte, Michael
AU  - Mian, Md Yeunus
AU  - Rezvanian, Sepideh
AU  - Sharmin, Dishary
AU  - Kovačević, Aleksandra
AU  - Savić, Miroslav
AU  - Cook, James M.
AU  - Sibille, Etienne
AU  - Prevot, Thomas D.
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5540
AB  - Chronic stress is a risk factor for Major Depressive Disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at α2-GABAA-Rs contributes to anxiolytic properties, α5-GABAA-Rs to cognitive functions, and α1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing α2- and α5-GABAA-Rs activity, but devoid of α1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side-effects. This study investigated the activity profiles and behavioral efficacy of two enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the α2-, α3-, α5-GABAA-Rs and α5-containing GABAA-Rs, respectively, and separately reduces immobility in the forced swim test and improves stress-induced spatial working memory deficits. Using unpredictable chronic mild stress (UCMS), we show that acute and chronic administration of GL-RM provide pro-cognitive effects, with mild efficacy on mood symptoms, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined α2-, α3-, α5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.
PB  - Springer Nature
T2  - Neuropsychopharmacology
T1  - Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress
VL  - 47
IS  - 9
SP  - 1608
EP  - 1619
DO  - 10.1038/s41386-022-01360-y
ER  - 

@article{
author = "Bernardo, Ashley and Lee, Philip and Marcotte, Michael and Mian, Md Yeunus and Rezvanian, Sepideh and Sharmin, Dishary and Kovačević, Aleksandra and Savić, Miroslav and Cook, James M. and Sibille, Etienne and Prevot, Thomas D.",
year = "2022",
abstract = "Chronic stress is a risk factor for Major Depressive Disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at α2-GABAA-Rs contributes to anxiolytic properties, α5-GABAA-Rs to cognitive functions, and α1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing α2- and α5-GABAA-Rs activity, but devoid of α1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side-effects. This study investigated the activity profiles and behavioral efficacy of two enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the α2-, α3-, α5-GABAA-Rs and α5-containing GABAA-Rs, respectively, and separately reduces immobility in the forced swim test and improves stress-induced spatial working memory deficits. Using unpredictable chronic mild stress (UCMS), we show that acute and chronic administration of GL-RM provide pro-cognitive effects, with mild efficacy on mood symptoms, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined α2-, α3-, α5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.",
publisher = "Springer Nature",
journal = "Neuropsychopharmacology",
title = "Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress",
volume = "47",
number = "9",
pages = "1608-1619",
doi = "10.1038/s41386-022-01360-y"
}

Bernardo, A., Lee, P., Marcotte, M., Mian, M. Y., Rezvanian, S., Sharmin, D., Kovačević, A., Savić, M., Cook, J. M., Sibille, E.,& Prevot, T. D.. (2022). Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress. in Neuropsychopharmacology
Springer Nature., 47(9), 1608-1619.
https://doi.org/10.1038/s41386-022-01360-y

Bernardo A, Lee P, Marcotte M, Mian MY, Rezvanian S, Sharmin D, Kovačević A, Savić M, Cook JM, Sibille E, Prevot TD. Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress. in Neuropsychopharmacology. 2022;47(9):1608-1619.
doi:10.1038/s41386-022-01360-y .

Bernardo, Ashley, Lee, Philip, Marcotte, Michael, Mian, Md Yeunus, Rezvanian, Sepideh, Sharmin, Dishary, Kovačević, Aleksandra, Savić, Miroslav, Cook, James M., Sibille, Etienne, Prevot, Thomas D., "Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress" in Neuropsychopharmacology, 47, no. 9 (2022):1608-1619,
https://doi.org/10.1038/s41386-022-01360-y . .