Antagonist activity of α‐substituted 4‐carboxyphenylglycine analogues at group I metabotropic glutamate receptors expressed in CHO cells
AJ Doherty, GL Collingridge… - British journal of …, 1999 - Wiley Online Library
AJ Doherty, GL Collingridge, DE Jane
British journal of pharmacology, 1999•Wiley Online LibraryWe have investigated the antagonist properties of 6 α‐substituted phenylglycine analogues
based on the structure of 4‐carboxyphenylglycine (4‐CPG) for group I metabotropic
glutamate receptors (mGlu1α and mGlu5a) permanently expressed in CHO cells.(S)‐4‐CPG
and (S)‐MCPG were the most selective mGlu1α receptor antagonists. Longer chain α‐
carbon substitutions resulted in a progressive loss of antagonist affinity at mGlu1α receptors
but not at mGlu5a receptors. Thus mGlu1α receptor antagonists require small aliphatic …
based on the structure of 4‐carboxyphenylglycine (4‐CPG) for group I metabotropic
glutamate receptors (mGlu1α and mGlu5a) permanently expressed in CHO cells.(S)‐4‐CPG
and (S)‐MCPG were the most selective mGlu1α receptor antagonists. Longer chain α‐
carbon substitutions resulted in a progressive loss of antagonist affinity at mGlu1α receptors
but not at mGlu5a receptors. Thus mGlu1α receptor antagonists require small aliphatic …
- We have investigated the antagonist properties of 6 α‐substituted phenylglycine analogues based on the structure of 4‐carboxyphenylglycine (4‐CPG) for group I metabotropic glutamate receptors (mGlu1α and mGlu5a) permanently expressed in CHO cells.
- (S)‐4‐CPG and (S)‐MCPG were the most selective mGlu1α receptor antagonists. Longer chain α‐carbon substitutions resulted in a progressive loss of antagonist affinity at mGlu1α receptors but not at mGlu5a receptors. Thus mGlu1α receptor antagonists require small aliphatic groups at the α‐position. α‐cyclopropyl‐4‐CPG showed a tendency towards mGlu5a selectivity, suggesting that bulky groups at this position may favour mGlu5a receptor antagonism.
- We demonstrate that the mGlu5a receptor displays agonist‐dependent antagonism. L‐glutamate‐induced Ca2+ release in mGlu5a receptor expressing cells was more susceptible to antagonism by cyclic α‐carbon derivatives than (S)‐3,5‐dihydroxyphenylglycine (DHPG)‐induced Ca2+ release in the same cell line.
- The data presented suggests that mGlu1α and mGlu5a receptors have different steric and/or conformational requirements for the binding of antagonists and different amino acids which could interact with agonists.
- These phenylglycine analogues could provide leads for the development of subtype selective antagonists.
British Journal of Pharmacology (1999) 126, 205–210; doi:10.1038/sj.bjp.0702297
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