2-(Carboxycyclopropyl)glycines: binding, neurotoxicity and induction of intracellular free Ca2+ increase

The excitatory actions of the eight stereoisomers of 2-(carboxycyclopropyl)glycine (CCG), conformationally rigid glutamate analogues, were analyzed for the glutamate receptor subtypes by means of binding assays with rat brain membranes. All CCG isomers inhibited the binding of [3H]3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid ([3H]CPP) to N-methyl-D-aspartate (NMDA) receptors. The (2S,3R,4S) isomer (L-CCG-IV) was the most potent agonist for the NMDA receptor and its binding potency was 17- and 790-fold higher than that of L-glutamate and NMDA, respectively. The (2S,3S,4R) isomer (L-CCG-III) showed a potent inhibitory activity for [3H]D-aspartate uptake. Further, L-CCG-IV caused a marked increase of intracellular free Ca2+ concentration [( Ca2+]i) and potent neurotoxicity in the single rat cerebral cortical neurons in vitro, and both were blocked effectively by the NMDA antagonists. Significant correlations were observed between neurotoxicity and the increase of [Ca2+]i and [3H]CPP binding affinity to the NMDA receptor.