The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABA(C) receptors. |
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Authors: | Mary Chebib Rujee K. Duke Robin D. Allan Graham A. R. Johnston |
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Affiliation: | a Faculty of Pharmacy, Department of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia b Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia |
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Abstract: | The pharmacological effects of the enantiomers of cis-3-aminocyclopentanecarboxylic acids ((+)- and (−)-CACP), the enantiomers of trans-3-aminocyclopentanecarboxylic acids ((+)- and (−)-TACP), and the enantiomers of 4-aminocyclopent-1-ene-1-carboxylic acids ((+)- and (−)-4-ACPCA) were studied on human homomeric ρ1 and ρ2 GABAC receptors expressed in Xenopus oocytes using two-electrode voltage clamp methods. These compounds are conformationally restricted analogues of γ-aminobutyric acid (GABA) held in a five-membered ring. (+)-TACP (EC50 (ρ1)=2.7±0.2 μM; EC50 (ρ2)=1.45±0.22 μM), (+)-CACP (EC50 (ρ1)=26.1±1.1 μM; EC50 (ρ2)=20.1±2.1 μM) and (−)-CACP (EC50 (ρ1)=78.5±3.5 μM; EC50 (ρ2)=63.8±23.3 μM) were moderately potent partial agonists at ρ1 and ρ2 GABAC receptors, while (−)-TACP (100 μM inhibited 56% and 62% of the current produced by 1 μM GABA at ρ1 and ρ2 receptors, respectively) was a weak partial agonist with low intrinsic activity at these receptors. In contrast, (+)-4-ACPCA (Ki (ρ1)=6.0±0.1 μM; Ki (ρ2)=4.7±0.3 μM) did not activate GABAC ρ1 and ρ2 receptors but potently inhibited the action of GABA at these receptors, while (−)-4-ACPCA had little effect as either an agonist or an antagonist. The affinity order at both GABAC ρ1 and ρ2 receptors was (+)-TACP>(+)-4-ACPCA(+)-CACP>(−)-CACP(−)-TACP(−)-4-ACPCA. This study shows that the cyclopentane and cyclopentene analogues of GABA affect GABAC receptors in a unique manner, defining a preferred stereochemical orientation of the amine and carboxylic acid groups when binding to GABAC receptors. This is exemplified by the partial agonist, (+)-TACP, and the antagonist, (+)-4-ACPCA. |
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Keywords: | γ-Aminobutyric acid (GABA) GABAC receptor Structure–activity relationship Cyclopentane and cyclopentene analogues of GABA Xenopus oocyte |
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