title: Evaluation of the activity of a novel metabotropic glutamate receptor antagonist (+/-)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) in the in vitro neonatal spinal cord and in an in vivo pain model.
abstract: The cyclobutylglycine (+/-)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) (LY393053) has been identified as a functionally potent metabotropic glutamate receptor antagonist. It is most potent on the two group I metabotropic glutamate receptors, 1alpha and 5alpha, with IC50 values of 1.0+/-0.4 microM and 1.6+/-1.4 microM, respectively. In this study, LY393053 has also been evaluated electrophysiologically on native group I metabotropic glutamate receptors in an in vitro spinal cord preparation as well as behaviourally, in a mouse model of visceral pain. LY393053 dose-dependently antagonised group I agonist, (RS)-3, 5-dihydroxyphenylglycine, or a broad-spectrum agonist (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation of spinal motoneurons. The apparent Kd values were estimated to be 0.3 microM against (RS)-3, 5-dihydroxyphenylglycine-induced depolarisation and 0.5 microM against (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation, respectively. On the other hand, the dorsal root-ventral root potential elicited at 8 x threshold was depressed by LY393053 with IC50 values of 9.0+/-0.7 microM and 12.7+/-1.7 microM on monosynaptic and polysynaptic responses, respectively. When investigated using the mouse acetic acid writhing test, LY393053 showed significant analgesic effects at doses of 1-10 mg/kg intraperitoneally. An ED50 value of 6.0 mg/kg was obtained in this test. By revealing a potent effect of LY393053 in antagonising the native group I metabotropic receptor-mediated responses in the spinal cord in rodents, and an antinociceptive efficacy in a mouse visceral pain model, these results, therefore, provide additional evidence in support of the analgesic potential of metabotropic glutamate receptor antagonists.
authors.affiliation: Eli Lilly & Co, Windlesham, Surrey, UK. CHEN_YING@lilly.com
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: G
authors.initials: G
authors.lastname: Bacon
authors.forename: E
authors.initials: E
authors.lastname: Sher
authors.forename: B P
authors.initials: BP
authors.lastname: Clark
authors.forename: M J
authors.initials: MJ
authors.lastname: Kallman
authors.forename: R A
authors.initials: RA
authors.lastname: Wright
authors.forename: B G
authors.initials: BG
authors.lastname: Johnson
authors.forename: D D
authors.initials: DD
authors.lastname: Schoepp
authors.forename: A E
authors.initials: AE
authors.lastname: Kingston
mesh_terms: D019342:Acetic Acid; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012118:Resorcinols / Q000494:pharmacology; D013116:Spinal Cord / Q000503:physiopathology*; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism
chemical_list: D018691:Excitatory Amino Acid Antagonists; C404526:LY393053; D018696:Neuroprotective Agents; D011422:Propionates; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C079215:3,5-dihydroxyphenylglycine; D019342:Acetic Acid; D005998:Glycine