(+)‐ and (‐)‐cis‐2‐Aminomethylcyclopropanecarboxylic Acids Show Opposite Pharmacology at Recombinant ρ1 and ρ2 GABAC Receptors

• Published in: Journal of neurochemistry 2000-12, Vol.75 (6), p.2602-2610
• Main Authors: Duke, Rujee K., Chebib, Mary, Balcar, Vladimir J., Allan, Robin D., Mewett, Kenneth N., Johnston, Graham A. R.
• Format: Article
• Language: English
• Subjects: (±)‐cis‐ and (±)‐trans‐2‐Aminomethylcyclopropanecarboxylic acids; Aminoacid receptors (glycine, glutamate, gaba); Biological and medical sciences; Cell receptors; Cell structures and functions; Fundamental and applied biological sciences. Psychology; GABAA receptors; GABAC receptors; Molecular and cellular biology; Molecular modeling; Xenopus oocytes
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2000.0752602.x

: The effects of the enantiomers of (±)‐CAMP and(±)‐TAMP [(±)‐cis‐ and(±)‐trans‐2‐aminomethylcyclopropanecarboxylic acids,respectively], which are cyclopropane analogues of GABA, were tested onGABAA and GABAC receptors expressed in Xenopuslaevis oocytes using two‐electrode voltage clamp methods. (+)‐CAMP wasfound to be a potent and full agonist at homooligomeric GABACreceptors (KD∼40 μM andImax∼100% at ρ1;KD∼17 μM and Imax∼100% at ρ2) but a very weak antagonist atα1β2γ2L GABAAreceptors. In contrast, (‐)‐CAMP was a very weak antagonist at bothα1β2γ2L GABAAreceptors and homooligomeric GABAC receptors (IC50∼900 μM at ρ1 and ∼400 μM atρ2). Furthermore, (+)‐CAMP appears to be a superior agonist tothe widely used GABAC receptor partial agonistcis‐4‐aminocrotonic acid (KD∼74μM and Imax∼78% at ρ1;KD∼70 μM and Imax∼82% at ρ2). (‐)‐TAMP was the most potent of thecyclopropane analogues on GABAC receptors (KD∼9 μM and Imax∼40% atρ1; KD∼3 μM andImax∼50‐60% at ρ2), but it was also amoderately potent GABAA receptor partial agonist(KD∼50‐60 μM and Imax∼50% at α1β2γ2LGABAA receptors). (+)‐TAMP was a less potent partial agonist atGABAC receptors (KD∼60 μM andImax∼40% at ρ1; KD∼30 μM and Imax∼60% atρ2) and a weak partial agonist atα1β2γ2L GABAAreceptors (KD∼500 μM andImax∼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 GABAC receptors.