Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagonists.
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.
Kingston
Ann E
AE
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. kingston_ann_e@lilly.com
Griffey
Kelly
K
Johnson
Michael P
MP
Chamberlain
Mary-Jo
MJ
Kelly
Gerald
G
Tomlinson
Rosemarie
R
Wright
Rebecca A
RA
Johnson
Bryan G
BG
Schoepp
Darryle D
DD
Harris
John R
JR
Clark
Barry P
BP
Baker
Richard S
RS
Tizzano
Joseph T
JT
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D051379:Mice; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D012640:Seizures / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology
C469332:2-amino-2-(3-carboxycyclobutyl)-3-(9H-xanthen-9-yl)propionic acid; C469331:2-amino-2-(4-carboxyphenyl)-3-(9H-xanthen-9-yl)propanoic acid; C469330:2-methyl-3-hydroxy-4-carboxyphenylglycine; D001565:Benzoates; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C404526:LY393053; D011422:Propionates; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D013876:Thiophenes; D014966:Xanthenes; C119517:alpha-thioxantylmethyl-4-carboxyphenylglycine; C453101:carboxyphenylglycine; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; C079215:3,5-dihydroxyphenylglycine; D000409:Alanine; D005998:Glycine