Antagonist activity of α-substituted 4-carboxyphenylglycine analogues at group I metabotropic glutamate receptors expressed in CHO cells
- Resource Type
- Authors
- Andrew J Doherty; David E Jane; Graham L. Collingridge
- Source
- British Journal of Pharmacology. 126:205-210
- Subject
- Pharmacology
Metabotropic receptor
Metabotropic glutamate receptor
APICA
Stereochemistry
Metabotropic glutamate receptor 5
Chemistry
Metabotropic glutamate receptor 6
Metabotropic glutamate receptor 1
Metabotropic glutamate receptor 2
HYDIA
- Language
- ISSN
- 0007-1188
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