Effect of α-(carboxycyclopropyl)glycines (CCG's), novel NMDA receptor agonists, on the intracellular Ca2+ concentration in cultured cortex neurons

We investigated the effect of eight conformationally rigid glutamate analogues (CCG isomers) on the intracellular free Ca^2+ concentration ([Ca^2+ ]_i ) in single rat cortex neurons, in vitro. The (2S,3R,4S) isomer (L-CCG-IV) increased [Ca^2+ ]_i most strongly (EC_50 = 0.16 μM). This activity was about 18-fold higher than that of L-glutamate and 130-fold higher than that of NMDA. The (2R,3S,4S) isomer (D-CCG-II) and the (2R,3S,4R) isomer (D-CCG-IV) had moderate activity. The remaining isomers showed low activity. The increases in [Ca^2+ ]_i which were induced by the CCG stereoisomers correlated well with the binding affinity of these isomers to the NMDA receptor. However, this good correlation was absent for both quisqualate and kainate receptors (1). In addition, we found that the CCG stereoisomers enhanced [[^^3 H]N-[1-(2-thienyl)cyclohexyl]piperidine ([^^3 H]TCP) binding activity to NMDA receptor-coupled cation channels. These results suggest that the CCG stereoisomers selectively bind to NMDA receptors, and also that L-CCG-IV is the most potent NMDA receptor agonist. 1) Effect of α-(carboxycyclopropyl)glycines (CCG's) on excitatory amino acid receptors. M.Kawai, K.Shimamoto, Y.Ohfune, and T.Ishihara. (at this meeting)