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Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog
dc.creator | Ping, Xingjie | |
dc.creator | Meyer, Michelle J. | |
dc.creator | Zahn, Nicolas M. | |
dc.creator | Golani, Lalit K. | |
dc.creator | Sharmin, Dishary | |
dc.creator | Pandey, Kamal P. | |
dc.creator | Revanian, Sepideh | |
dc.creator | Mondal, Prithu | |
dc.creator | Jin, Xiaoming | |
dc.creator | Arnold, Leggy A. | |
dc.creator | Cerne, Rok | |
dc.creator | Cook, James M. | |
dc.creator | Divović, Branka | |
dc.creator | Savić, Miroslav | |
dc.creator | Lippa, Arnold | |
dc.creator | Smith, Jodi L. | |
dc.creator | Witkin, Jeffrey M. | |
dc.date.accessioned | 2023-02-14T15:34:02Z | |
dc.date.available | 2023-02-14T15:34:02Z | |
dc.date.issued | 2023 | |
dc.identifier.issn | 0272-4391 | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/4427 | |
dc.description.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. | |
dc.publisher | John Wiley and Sons Inc | |
dc.relation | Granting agencies for support: DA‐043204 and NS‐076517 and the National Science Foundation, Division of Chemistry [Grant CHE‐1625735] | |
dc.relation | 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 | |
dc.relation | info:eu-repo/grantAgreement/MESTD/inst-2020/200161/RS// | |
dc.rights | restrictedAccess | |
dc.source | Drug Development Research | |
dc.subject | KRM-II-81 | |
dc.subject | anticonvulsant | |
dc.subject | deuterated analog | |
dc.title | Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog | |
dc.type | article | |
dc.rights.license | ARR | |
dc.citation.volume | 84 | |
dc.citation.issue | 3 | |
dc.citation.rank | M21~ | |
dc.identifier.wos | 000928830200001 | |
dc.identifier.doi | 10.1002/ddr.22042 | |
dc.identifier.pmid | 36748904 | |
dc.identifier.scopus | 2-s2.0-85147501608 | |
dc.type.version | publishedVersion |