Antagonist activity of a-substituted 4-carboxyphenylglycine analogues at group I metabotropic glutamate receptors expressed in CHO cells

Abstract

1 We have investigated the antagonist properties of 6 -substituted phenylglycine analogues based on the structure of 4-carboxyphenylglycine (4-CPG) for group I metabotropic glutamate receptors (mGlui, and mGlu5a) permanently expressed in CHO cells. 2 (S)-4-CPG and (S)-MCPG were the most selective mGlu, receptor antagonists. Longer chain xcarbon substitutions resulted in a progressive loss of antagonist affinity at mGIu receptors but not at mGIu5a receptors. Thus rnGlu, receptor antagonists require small aliphatic groups at the Deposition. a-cyclopropyl-4-CPG showed a tendency towards mGlu5a selectivity, suggesting that bulky groups at this position may favour mGIu5a receptor antagonism. 3 We demonstrate that the mGlu3a receptor displays agonist-dependent antagonism. L-glutamateinduced Ca2+ release in mGlu5a receptor expressing cells was more susceptible to antagonism by cyclic a-carbon derivatives than (S)-3,5-dihydroxyphenylglycine (DHPG)-induced Ca2+ release in the same cell line. 4 The data presented suggests that mGlu1:( and mGluJa receptors have different steric and/or conformational requirements for the binding of antagonists and different amino acids which could interact with agonists. 5 These phenylglycine analogues could provide leads for the development of subtype selective antagonists. © 1999 Stockton Press All rights reserved (.