(+)- and (-)-cis-2-Aminomethylcyclopropanecarboxy acids show opposite pharmacology at recombinant ρ1 and ρ2 GABAC receptors

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 similar to 40 muM and I-max similar to 100% at rho (1); K-D similar to 17 muM and I-max similar to 100% at rho2) 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 (IC50 similar to 900 muM at rho (1) and similar to 400 muM 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 similar to 74 muM and I-max similar to 78% at rho (1); K-D similar to 70 muM and I-max similar to 82% at rho (2)). (-)-TAMP was the most potent of the cyclopropane analogues on GABA, receptors (K-D similar to9 muM and I-max similar to 40% at rho (1); K-D similar to3 muM and I-max similar to 50-60% at rho (2)), but it was also a moderately potent GABA(A) receptor partial agonist (K-D similar to 50-60 muM and I-max similar to 50% at alpha (1)beta (2)gamma (2L) GABA(A) receptors). (+)-TAMP was a less potent partial agonist at GABA(C) receptors (K-D similar to 60 muM and I-max similar to 40% at rho (1); K-D similar to 30 muM and I-max similar to 60% at rho (2)) and a weak partial agonist at alpha (1)beta (2)gamma (2L) GABA(A) receptors (K-D similar to 500 muM and I-max similar to 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.