The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABA(C) receptors

Eur J Pharmacol. 2001 Nov 2;430(2-3):185-92. doi: 10.1016/s0014-2999(01)01390-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Membrane Potentials / drug effects
  • Oocytes
  • Receptors, GABA / drug effects*
  • Receptors, GABA / genetics
  • Receptors, GABA / physiology
  • Recombinant Proteins / drug effects
  • Stereoisomerism
  • Xenopus laevis
  • gamma-Aminobutyric Acid / analogs & derivatives
  • gamma-Aminobutyric Acid / pharmacology*


  • Cyclopentanes
  • GABA-C receptor
  • Receptors, GABA
  • Recombinant Proteins
  • gamma-Aminobutyric Acid