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

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The pharmacology of (2 S,4 R)-4-methylglutamic acid, (2 S,4 S)-4-methylglutamic acid and ( S)- and ( R)-4-methyleneglutamic acids (obtained in high chemical and enantiomeric purity from racemic 4-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, (2 S,4 R)-4-methylglutamic acid and (2 S,4 S)-4-methylglutamic acid were both shown to be selective for kainic acid receptors and mGlu receptors (subtypes 1 α and 2), respectively, whereas ( 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 1 α 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.