Show simple item record

dc.creatorSavić, Miroslav
dc.creatorHuang, Shengming
dc.creatorFurtmueller, Roman
dc.creatorClayton, Terry
dc.creatorHuck, Sigismund
dc.creatorObradović, Dragan I.
dc.creatorUgrešić, Nenad
dc.creatorSieghart, Werner
dc.creatorBokonjić, Dubravko
dc.creatorCook, James M.
dc.date.accessioned2019-09-02T11:12:51Z
dc.date.available2019-09-02T11:12:51Z
dc.date.issued2008
dc.identifier.issn0893-133X
dc.identifier.urihttp://farfar.pharmacy.bg.ac.rs/handle/123456789/1048
dc.description.abstractClassical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABAA receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABAA receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABAA receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.en
dc.publisherNature Publishing Group, London
dc.relationNIMH NIH HHS 46851
dc.rightsopenAccess
dc.sourceNeuropsychopharmacology
dc.subjectGABA(A)en
dc.subjectbenzodiazepineen
dc.subjectsedationen
dc.subjectanxietyen
dc.subjectataxiaen
dc.subjectsubtype-selectivityen
dc.titleAre GABA(A) receptors containing alpha 5 Subunits contributing to the sedative properties of benzodiazepine site agonists?en
dc.typearticle
dc.rights.licenseARR
dcterms.abstractОбрадовић, Драган И.; Хуанг, Схенгминг; Фуртмуеллер, Роман; Цлаyтон, Террy; Угрешић, Ненад; Бокоњић, Дубравко; Цоок, Јамес М.; Сиегхарт, Wернер; Хуцк, Сигисмунд; Савић, Мирослав;
dc.citation.volume33
dc.citation.issue2
dc.citation.spage332
dc.citation.epage339
dc.citation.other33(2): 332-339
dc.citation.rankaM21
dc.identifier.wos000251538100014
dc.identifier.doi10.1038/sj.npp.1301403
dc.identifier.pmid17392731
dc.identifier.scopus2-s2.0-36949012960
dc.identifier.fulltexthttp://farfar.pharmacy.bg.ac.rs//bitstream/id/37/1046.pdf
dc.identifier.rcubconv_1941
dc.type.versionpublishedVersion


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record