Potent NMDA-like actions and potentiation of glutamate responses by conformational variants of a glutamate analogue in the rat spinal cord

Abstract

1. Neuropharmacological actions of all possible-state isomers of alpha-(carboxycyclopropyl)glycine (CCG), conformationally restricted analogues of glutamate, were examined for electrophysiological effects in the isolated spinal cord of the newborn rat. 2. Eight CCG stereoisomers demonstrated a large variety of depolarizing activities. Among them, the (2R, 3S, 4S) isomers of CCG (D-CCG-II) showed the most potent depolarizing activity, followed by the (2S, 3R, 4S) isomer (L-CCG-IV). 3. The depolarization evoked by L-CCG-IV, D-CCG-II and other D-CCG isomers was effectively depressed by N-methyl-D-aspartate (NMDA) antagonists. D-CCG-II was about 5 times more potent than NMDA in causing a depolarization. 4. The (2S, 3S, 4S) isomer of CCG (L-CCG-I) was more potent than L-glutamate in causing a depolarization of spinal motoneurones. The depolarization was slightly depressed by NMDA antagonists, but residual amplitudes of responses to L-CCG-I in the presence of NMDA antagonists We almost insensitive to 6,7-dinitro-quinoxaline-2,3-dione (DNQX) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), suggesting that L-CCG-I might be a novel potent agonist. 5. After application of the (2S, 3S, 4R) isomer of CCG (L-CCG-III), responses to L-glutamate, D- and L-aspartate were markedly enhanced. The enhancement lasted for a period of several hours without a further application of L-CCG-III. 6. L-CCG-III also caused a depolarization, but it seemed unlikely that the potentiation of the glutamate response was directly related to the depolarization evoked by L-CCG-III. 7. The potentiation might be due to inhibition of uptake processes, but L-CCG-III was superior to L-(-)-threo-3-hydroxyaspartate, a potent uptake inhibitor of L-glutamate and L-aspartate, in enhancing the response to L-glutamate in terms of amplitude and duration of responses. 8. CCG isomers should provide useful pharmacological tools for analysis of glutamate neurotransmitter systems.