title: The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABA(C) receptors.
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 rho(1) and rho(2) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp methods. These compounds are conformationally restricted analogues of gamma-aminobutyric acid (GABA) held in a five-membered ring. (+)-TACP (EC(50) (rho(1))=2.7+/-0.2 microM; EC(50) (rho(2))=1.45+/-0.22 microM), (+)-CACP (EC(50) (rho(1))=26.1+/-1.1 microM; EC(50) (rho(2))=20.1+/-2.1 microM) and (-)-CACP (EC(50) (rho(1))=78.5+/-3.5 microM; EC(50) (rho(2))=63.8+/-23.3 microM) were moderately potent partial agonists at rho(1) and rho(2) GABA(C) receptors, while (-)-TACP (100 microM inhibited 56% and 62% of the current produced by 1 microM GABA at rho(1) and rho(2) receptors, respectively) was a weak partial agonist with low intrinsic activity at these receptors. In contrast, (+)-4-ACPCA (K(i) (rho(1))=6.0+/-0.1 microM; K(i) (rho(2))=4.7+/-0.3 microM) did not activate GABA(C) rho(1) and rho(2) 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 GABA(C) rho(1) and rho(2) receptors was (+)-TACP>(+)-4-ACPCA >> (+)-CACP>(-)-CACP >> (-)-TACP >> (-)-4-ACPCA. This study shows that the cyclopentane and cyclopentene analogues of GABA affect GABA(C) receptors in a unique manner, defining a preferred stereochemical orientation of the amine and carboxylic acid groups when binding to GABA(C) receptors. This is exemplified by the partial agonist, (+)-TACP, and the antagonist, (+)-4-ACPCA.
authors.affiliation: Faculty of Pharmacy, Department of Pharmacology, The University of Sydney, NSW 2006, Sydney, Australia. maryc@pharm.usyd.edu.au
authors.forename: M
authors.initials: M
authors.lastname: Chebib
authors.forename: R K
authors.initials: RK
authors.lastname: Duke
authors.forename: R D
authors.initials: RD
authors.lastname: Allan
authors.forename: G A
authors.initials: GA
authors.lastname: Johnston
mesh_terms: D000818:Animals; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes; D018079:Receptors, GABA / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000187:drug effects; D013237:Stereoisomerism; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D003517:Cyclopentanes; C087200:GABA-C receptor; D018079:Receptors, GABA; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid