Antagonist activity of alpha-substituted 4-carboxyphenylglycine analogues at group I metabotropic glutamate receptors expressed in CHO cells.
1. We have investigated the antagonist properties of 6 alpha-substituted phenylglycine analogues based on the structure of 4-carboxyphenylglycine (4-CPG) for group I metabotropic glutamate receptors (mGlu1alpha and mGlu5a) permanently expressed in CHO cells. 2. (S)-4-CPG and (S)-MCPG were the most selective mGlu1alpha receptor antagonists. Longer chain alpha-carbon substitutions resulted in a progressive loss of antagonist affinity at mGlu1alpha receptors but not at mGlu5a receptors. Thus mGlu1alpha receptor antagonists require small aliphatic groups at the alpha-position. Alpha-cyclopropyl-4-CPG showed a tendency towards mGlu5a selectivity, suggesting that bulky groups at this position may favour mGlu5a receptor antagonism. 3. 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 alpha-carbon derivatives than (S)-3,5-dihydroxyphenylglycine (DHPG)-induced Ca2+ release in the same cell line. 4. The data presented suggests that mGlu1alpha and mGlu5a 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.
Department of Anatomy, School of Medical Sciences, University of Bristol, England, UK. a.doherty@bristol.ac.uk
A J
AJ
Doherty
G L
GL
Collingridge
D E
DE
Jane
D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010648:Phenylacetates / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology
C107349:2-chloro-5-hydroxyphenylglycine; D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D010648:Phenylacetates; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C078245:4-carboxy-3-hydroxyphenylglycine; D018698:Glutamic Acid; C079215:3,5-dihydroxyphenylglycine; C079693:4-carboxyphenylglycine; D002118:Calcium; D005998:Glycine