ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
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 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2000.0752602.x
