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dc.creatorKnutson, Daniel
dc.creatorKodali, Revathi
dc.creatorDivović, Branka
dc.creatorTreven, Marco
dc.creatorStephen, Michael
dc.creatorZahn, Nicolas
dc.creatorDobričić, Vladimir
dc.creatorHuber, Alec
dc.creatorMeirelles, Matheus
dc.creatorVerma, Ranjit
dc.creatorWimmer, Laurin
dc.creatorWitzigmann, Christopher
dc.creatorArnold, Leggy
dc.creatorChiou, Lih-Chu
dc.creatorErnst, Margot
dc.creatorMihovilović, Marko D.
dc.creatorSavić, Miroslav
dc.creatorSieghart, Werner
dc.creatorCook, James M.
dc.date.accessioned2019-09-02T12:06:00Z
dc.date.available2019-09-02T12:06:00Z
dc.date.issued2018
dc.identifier.issn0022-2623
dc.identifier.urihttps://farfar.pharmacy.bg.ac.rs/handle/123456789/3147
dc.description.abstractRecent reports indicate that alpha 6/beta 2/3 gamma 2 GABA(A)R selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally alpha 6/beta 2/3 gamma 2 GABA(A)R selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA(A)R a alpha 6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs and were functionally silent at diazepam sensitive alpha 6/beta 2/3 gamma 2 GABA(A)Rs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA(A)R alpha 6/beta 2/3 gamma 2 subtypes.en
dc.publisherAmer Chemical Soc, Washington
dc.relationNational Institutes of Health (NIH) - R01 NS076517
dc.rightsrestrictedAccess
dc.sourceJournal of Medicinal Chemistry
dc.titleDesign and Synthesis of Novel Deuterated Ligands Functionally Selective for the gamma-Aminobutyric Acid Type A Receptor (GABA(A)R) alpha 6 Subtype with Improved Metabolic Stability and Enhanced Bioavailabilityen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractКнутсон, Даниел; Верма, Рањит; Миховиловић, Марко Д.; Тревен, Марцо; Цоок, Јамес М.; Кодали, Реватхи; Дивовић, Бранка; Захн, Ницолас; Савић, Мирослав; Ернст, Маргот; Aрнолд, Леггy; Хубер, Aлец; Wиммер, Лаурин; Добричић, Владимир; Сиегхарт, Wернер; Меиреллес, Матхеус; Степхен, Мицхаел; Цхиоу, Лих-Цху; Wитзигманн, Цхристопхер;
dc.citation.volume61
dc.citation.issue6
dc.citation.spage2422
dc.citation.epage2446
dc.citation.other61(6): 2422-2446
dc.citation.rankaM21
dc.identifier.wos000428356600015
dc.identifier.doi10.1021/acs.jmedchem.7b01664
dc.identifier.pmid29481759
dc.identifier.scopus2-s2.0-85044203204
dc.type.versionpublishedVersion


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