MOLECULAR PHARMACOLOGY OF 4-SUBSTITUTED GLUTAMIC-ACID ANALOGS AT IONOTROPIC AND METABOTROPIC EXCITATORY AMINO-ACID RECEPTORS

The pharmacology of (2S,4R)-4-methylglutamic acid, (2S,4S)-4-methylglu tamic acid and (S)- and (R)-4-methyleneglutamic acids (obtained in hig h chemical and enantiomeric purity from racemic 3-methyleneglutamic ac id by chiral HPLC using a Crownpak CR(+) column), was examined in bind ing experiments using rat brain ionotropic glutamate receptors, and in functional assays using cloned metabotropic glutamate (mGlu) receptor s. As a notable result of these studies, (2S,4R)-4-methylglutamic acid and (2S,3S)-4-methylglutamic acid were shown to be selective for kain ic acid receptors and mGlu receptors (subtypes 1 alpha and 2), respect ively, when as (S)-4-methyleneglutamic acid showed high but rather non -selective affinity for the amino-3-(3-hydroxy-5-methylisoxazol-4-yl)p ropionic acid (AMPA), kainic acid, NMDA and mGlu receptors (subtypes I cy and 2). Although none of the compounds were specific for any of the receptor subtypes, the results demonstrate that each of these structu rally related compounds has a distinct pharmacological profile. (C) 19 97 Elsevier Science B.V.