title: Γ-aminobutyric acid(C) (GABAC) selective antagonists derived from the bioisosteric modification of 4-aminocyclopent-1-enecarboxylic acid: amides and hydroxamates.
abstract: Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABAC, the most potent being 4-ACPHA (10a, IC50 = 13 μM) and 4-ACPAM (11a, IC50 = 10 μM). This provides evidence that a zwitterionic structure is not essential for GABAC antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding.
authors.affiliation: Adrien Albert Laboratory of Medicinal Chemistry, Pharmacology, University of Sydney , NSW, Australia.
authors.forename: Katherine E S
authors.initials: KE
authors.lastname: Locock
authors.forename: Izumi
authors.initials: I
authors.lastname: Yamamoto
authors.forename: Priscilla
authors.initials: P
authors.lastname: Tran
authors.forename: Jane R
authors.initials: JR
authors.lastname: Hanrahan
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
authors.forename: Robin D
authors.initials: RD
authors.lastname: Allan
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D018079:Receptors, GABA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D000577:Amides; D003517:Cyclopentanes; D018756:GABA Antagonists; C087200:GABA-C receptor; D006877:Hydroxamic Acids; D018079:Receptors, GABA