Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog
Само за регистроване кориснике
2023
Аутори
Ping, XingjieMeyer, 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.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
KRM-II-81 / anticonvulsant / deuterated analogИзвор:
Drug Development Research, 2023, 84, 3Издавач:
- John Wiley and Sons Inc
Финансирање / пројекти:
- Granting agencies for support: DA‐043204 and NS‐076517 and the National Science Foundation, Division of Chemistry [Grant CHE‐1625735]
- The UW‐Milwaukee Shimadzu Laboratory for Advanced and Applied Analytical Chemistry and support from the Milwaukee Institute of Drug Discovery and the University of Wisconsin‐Milwaukee Research Foundation
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200161 (Универзитет у Београду, Фармацеутски факултет) (RS-MESTD-inst-2020-200161)
DOI: 10.1002/ddr.22042
ISSN: 0272-4391
PubMed: 36748904
WoS: 000928830200001
Scopus: 2-s2.0-85147501608
Институција/група
PharmacyTY - 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 . .