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Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA(A) receptors containing the alpha 5 subunit
dc.creator | Timić-Stamenić, Tamara | |
dc.creator | Poe, Michael M. | |
dc.creator | Rehman, Sabah | |
dc.creator | Santrač, Anja | |
dc.creator | Divović, Branka | |
dc.creator | Scholze, Petra | |
dc.creator | Ernst, Margot | |
dc.creator | Cook, James M. | |
dc.creator | Savić, Miroslav | |
dc.date.accessioned | 2019-09-02T11:53:07Z | |
dc.date.available | 2019-09-02T11:53:07Z | |
dc.date.issued | 2016 | |
dc.identifier.issn | 0014-2999 | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/2631 | |
dc.description.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. | en |
dc.publisher | Elsevier Science BV, Amsterdam | |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175076/RS// | |
dc.rights | openAccess | |
dc.source | European Journal of Pharmacology | |
dc.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 | en |
dc.type | article | |
dc.rights.license | ARR | |
dcterms.abstract | Тимић-Стаменић, Тамара; Пое, Мицхаел М.; Ернст, Маргот; Дивовић, Бранка; Сантрач, Aња; Цоок, Јамес М.; Сцхолзе, Петра; Рехман, Сабах; Савић, Мирослав; | |
dc.citation.volume | 791 | |
dc.citation.spage | 433 | |
dc.citation.epage | 443 | |
dc.citation.other | 791: 433-443 | |
dc.citation.rank | M22 | |
dc.identifier.wos | 000388827700047 | |
dc.identifier.doi | 10.1016/j.ejphar.2016.09.016 | |
dc.identifier.pmid | 27639297 | |
dc.identifier.scopus | 2-s2.0-84988476311 | |
dc.identifier.fulltext | https://farfar.pharmacy.bg.ac.rs//bitstream/id/1309/2629.pdf | |
dc.type.version | publishedVersion |