Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagonists.

Abstract

A series of novel group I metabotropic glutamate receptor (mGlu) antagonists have been designed on the basis of the 4-carboxyphenylglycine pharmacophore. The compounds are either mGlu1 receptor selective or equipotent for both mGlu1 and mGlu5 receptors and have IC(50) values ranging from 1 to 30 microM determined by phosphoinositide hydrolysis (PI) assay in vitro. All the compounds produced dose-dependent inhibition of group I mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced limbic seizure responses in mice with ED(50) values ranging from 9 nmol for LY393053 to 138 nmol for LY339840 after intracerebroventricular injection and were more potent than the mGlu1 receptor antagonist 1-aminoindan-1,5-dicarboxylic acid (ED(50)=477 nmol). Further antagonist actions were also demonstrated in a model of (RS)-DHPG-induced PI hydrolysis in vivo such that LY367385 and the active cis isomer of LY393053 produced dose-dependent inhibition of PI responses in both cerebellum and hippocampus. Cis LY393053 also inhibited hippocampal PI responses when administered intraperitoneally at a dose of 30 mg/kg. These compounds define a new series of group I mGlu receptor antagonists which may serve as useful experimental tools.

• Authors: Ann E Kingston, Kelly Griffey, Michael P Johnson, Mary-Jo Chamberlain, Gerald Kelly, Rosemarie Tomlinson, Rebecca A Wright, Bryan G Johnson, Darryle D Schoepp, John R Harris, Barry P Clark, Richard S Baker, Joseph T Tizzano
• Journal: Neuroscience letters (Neurosci Lett) Vol. 330 Issue 2 Pg. 127-30 (Sep 20 2002) ISSN: 0304-3940 [Print] Ireland
• PMID: 12231428 (Publication Type: Journal Article)

Chemical References

• 2-amino-2-(3-carboxycyclobutyl)-3-(9H-xanthen-9-yl)propionic acid
• 2-amino-2-(4-carboxyphenyl)-3-(9H-xanthen-9-yl)propanoic acid
• 2-methyl-3-hydroxy-4-carboxyphenylglycine
• Benzoates
• Excitatory Amino Acid Agonists
• Excitatory Amino Acid Antagonists
• LY393053
• Propionates
• Receptors, Metabotropic Glutamate
• Resorcinols
• Thiophenes
• Xanthenes
• alpha-thioxantylmethyl-4-carboxyphenylglycine
• carboxyphenylglycine
• metabotropic glutamate receptor type 1
• alpha-methyl-4-carboxyphenylglycine
• 3,5-dihydroxyphenylglycine
• Alanine
• Glycine

Topics

• Alanine (analogs & derivatives, pharmacology)
• Animals
• Benzoates (pharmacology)
• Cerebellum (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Drug Interactions
• Excitatory Amino Acid Agonists (pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Glycine (analogs & derivatives, chemistry, pharmacology)
• Hippocampus (drug effects, metabolism)
• Inhibitory Concentration 50
• Mice
• Propionates (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Metabotropic Glutamate (agonists, antagonists & inhibitors, metabolism)
• Resorcinols (pharmacology)
• Seizures (prevention & control)
• Structure-Activity Relationship
• Thiophenes (pharmacology)
• Xanthenes (pharmacology)