(+)- and (-)-cis-2-aminomethylcyclopropanecarboxylic acids show opposite pharmacology at recombinant rho(1) and rho(2) GABA(C) receptors

J Neurochem. 2000 Dec;75(6):2602-10. doi: 10.1046/j.1471-4159.2000.0752602.x.

Abstract

The effects of the enantiomers of (+/-)-CAMP and (+/-)-TAMP [(+/-)-cis- and (+/-)-trans-2-aminomethylcyclopropanecarboxylic acids, respectively], which are cyclopropane analogues of GABA, were tested on GABA(A) and GABA(C) receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp methods. (+)-CAMP was found to be a potent and full agonist at homooligomeric GABA(C) receptors (K:(D) approximately 40 microM: and I:(max) approximately 100% at rho(1); K:(D) approximately 17 microM: and I:(max) approximately 100% at rho(2)) but a very weak antagonist at alpha(1)beta(2)gamma(2L) GABA(A) receptors. In contrast, (-)-CAMP was a very weak antagonist at both alpha(1)beta(2)gamma(2L) GABA(A) receptors and homooligomeric GABA(C) receptors (IC(50) approximately 900 microM: at rho(1) and approximately 400 microM: at rho(2)). Furthermore, (+)-CAMP appears to be a superior agonist to the widely used GABA(C) receptor partial agonist cis-4-aminocrotonic acid (K:(D) approximately 74 microM: and I:(max) approximately 78% at rho(1); K:(D) approximately 70 microM: and I:(max) approximately 82% at rho(2)). (-)-TAMP was the most potent of the cyclopropane analogues on GABA(C) receptors (K:(D) approximately 9 microM: and I:(max) approximately 40% at rho(1); K:(D) approximately 3 microM: and I:(max) approximately 50-60% at rho(2)), but it was also a moderately potent GABA(A) receptor partial agonist (K:(D) approximately 50-60 microM: and I:(max) approximately 50% at alpha(1)beta(2)gamma(2L) GABA(A) receptors). (+)-TAMP was a less potent partial agonist at GABA(C) receptors (K:(D) approximately 60 microM: and I:(max) approximately 40% at rho(1); K:(D) approximately 30 microM: and I:(max) approximately 60% at rho(2)) and a weak partial agonist at alpha(1)beta(2)gamma(2L) GABA(A) receptors (K:(D) approximately 500 micro: and I:(max) approximately 50%). None of the isomers of (+/-)-CAMP and (+/-)-TAMP displayed any interaction with GABA transport at the concentrations tested. Molecular modeling based on the present results provided new insights into the chiral preferences for either agonism or antagonism at GABA(C) receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Cyclic / pharmacology*
  • Animals
  • Binding, Competitive / drug effects
  • Brain / metabolism
  • Cells, Cultured
  • Crotonates / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Design
  • GABA Agonists / pharmacology*
  • GABA-A Receptor Agonists*
  • Humans
  • In Vitro Techniques
  • Models, Molecular
  • Oocytes / cytology
  • Oocytes / metabolism
  • Receptors, GABA / genetics
  • Receptors, GABA / metabolism*
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism
  • Recombinant Proteins / agonists
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transfection
  • Xenopus laevis
  • gamma-Aminobutyric Acid / pharmacokinetics

Substances

  • Amino Acids, Cyclic
  • Crotonates
  • GABA Agonists
  • GABA-A Receptor Agonists
  • GABA-C receptor
  • Receptors, GABA
  • Receptors, GABA-A
  • Recombinant Proteins
  • 4-aminocrotonic acid
  • 2-(aminomethyl)cyclopropanecarboxylic acid
  • gamma-Aminobutyric Acid