(+)‐ and (‐)‐ cis ‐2‐Aminomethylcyclopropanecarboxylic Acids Show Opposite Pharmacology at Recombinant ρ 1 and ρ 2 GABA C 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 onGABA A and GABA C receptors expressed in Xenopuslaevis oocytes using two‐electrode voltage clamp methods. (+)‐CAMP wasfound to be a potent and full agonist at homooligomeric GABA C receptors ( K D ∼40 μ M and I max ∼100% at ρ 1 ; K D ∼17 μ M and I max ∼100% at ρ 2 ) but a very weak antagonist atα 1 β 2 γ 2L GABA A receptors. In contrast, (‐)‐CAMP was a very weak antagonist at bothα 1 β 2 γ 2L GABA A receptors and homooligomeric GABA C receptors (IC 50 ∼900 μ M at ρ 1 and ∼400 μ M atρ 2 ). Furthermore, (+)‐CAMP appears to be a superior agonist tothe widely used GABA C receptor partial agonist cis ‐4‐aminocrotonic acid ( K D ∼74μ M and I max ∼78% at ρ 1 ; K D ∼70 μ M and I max ∼82% at ρ 2 ). (‐)‐TAMP was the most potent of thecyclopropane analogues on GABA C receptors ( K D ∼9 μ M and I max ∼40% atρ 1 ; K D ∼3 μ M and I max ∼50‐60% at ρ 2 ), but it was also amoderately potent GABA A receptor partial agonist( K D ∼50‐60 μ M and I max ∼50% at α 1 β 2 γ 2L GABA A receptors). (+)‐TAMP was a less potent partial agonist atGABA C receptors ( K D ∼60 μ M and I max ∼40% at ρ 1 ; K D ∼30 μ M and I max ∼60% atρ 2 ) and a weak partial agonist atα 1 β 2 γ 2L GABA A receptors ( K D ∼500 μ M and I max ∼50%). None of the isomers of (±)‐CAMP and(±)‐TAMP displayed any interaction with GABA transport at theconcentrations tested. Molecular modeling based on the present resultsprovided new insights into the chiral preferences for either agonism orantagonism at GABA C receptors.