title: GABA analogues derived from 4-aminocyclopent-1-enecarboxylic acid.
abstract: The incorporation of extra binding groups onto known ligands is a powerful tool for the development of more potent and selective agents at target sites such as the GABA receptors. In the present work we have attempted to build on the activity of the know potent GABA(A) agonist 4-ACP-3-CA and its cis and trans saturated analogues CACP and TACP. We have investigated reactions to add thiol substituents to the alpha,beta-unsaturated system of 4-ACP-3-CA. The reaction was successful with a limited number of thiols but gave products of mixed stereochemistry. The resultant thioether amino acids were screened for activity at human recombinant alpha(1)beta(2) gamma(2L) GABA(A) receptors. The most interesting derivative was the benzylthioether which acted as an antagonist with an IC(50) of 42 microM for the inhibition of a GABA EC(50) dose (50 microM). This study has shown that GABA analogues derived by thiol addition to 4-aminocyclopent-1-enecarboxylic acid display interesting antagonist activity at the alpha(1)beta(2)gamma(2L) GABA(A) receptor.
authors.affiliation: The Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Katherine E S
authors.initials: KE
authors.lastname: Locock
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
authors.forename: Robin D
authors.initials: RD
authors.lastname: Allan
mesh_terms: D000598:Amino Acids, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006801:Humans; D018079:Receptors, GABA / Q000737:chemistry / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000598:Amino Acids, Cyclic; D003509:Cyclohexanecarboxylic Acids; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C087200:GABA-C receptor; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; C010124:4-aminocyclohexanecarboxylic acid