New potent excitatory amino acids and marked potentiation of glutamate responses: Pharmacology of conformationally restricted glutamate analogues

Abstract

Eight isomers of α-(carboxycyclopropyl)glycine (CCG) which are conformationally restricted analogues of glutamate, demonstrated a large variety of depolarizing activities in the newborn rat spinal motoneurone. From these compounds, novel potent N-methyl-D-aspartic acid (NMDA) type agonists and some pharmacologically active compounds were found. The (2R, 3S, 4S) isomer of CCG (D-CCG-II) was a NMDA-type agonist and was much more potent than NMDA. The (2S, 3R, 4S) isomer of CCG (L-CCG-IV) is an L-glutamate analogue with a folded form and activates significantly NMDA-type receptors, leading to a conclusion that a preferred conformation of L-glutamate for activating NMDA-type receptors is a folded form. All D-isomers activated NMDA-type receptors. After a single application of the (2S,3S,4R) isomer of CCG (L-CCG-III), excitatory responses to L-glutamate were markedly enhanced. This enhancement lasted for more than several hours without a further application of L-CCG-III. Thus, CCG isomers would be expected to provide useful information about elucidating the function of the glutamate receptor.