Molecular pharmacology of 4-substituted glutamic acid analogues at ionotropic and metabotropic excitatory amino acid receptors

The pharmacology of (2S,4R)-4-methylglutamic acid, (2S,4S)-4-methylglutamic acid and (S)- and (R)-4-methyleneglutamic acids (obtained in high chemical and enantiomeric purity from racemic 3-methyleneglutamic acid by chiral HPLC using a Crownpak CR(+) column), was examined in binding experiments using rat brain ionotropic glutamate receptors, and in functional assays using cloned metabotropic glutamate (mGlu) receptors. As a notable result of these studies, (2S,4R)-4-methylglutamic acid and (2S,3S)-4-methylglutamic acid were shown to be selective for kainic acid receptors and mGlu receptors (subtypes 1 alpha and 2), respectively, when as (S)-4-methyleneglutamic acid showed high but rather non-selective affinity for the (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), kainic acid, NMDA and mGlu receptors (subtypes Icy and 2). Although none of the compounds were specific for any of the receptor subtypes, the results demonstrate that each of these structurally related compounds has a distinct pharmacological profile. (C) 1997 Elsevier Science B.V.