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

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

doi:10.1016/s0304-3940(02)00751-6

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

Neurosci Lett. 2002 Sep 20;330(2):127-30. doi: 10.1016/s0304-3940(02)00751-6.

Authors

Ann E Kingston¹, 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

Affiliation

¹ Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. [email protected]

PMID: 12231428
DOI: 10.1016/s0304-3940(02)00751-6

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.

MeSH terms

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

Substances

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