Evaluation Of The Activity Of A Novel Metabotropic Glutamate Receptor Antagonist (+/-)-2-Amino-2-(3-Cis And Trans-Carboxycyclobutyl-3-(9-Thioxanthyl Acid) In The In Vitro Neonatal Spinal Cord And In An In Vivo Pain Model

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, 1 alpha and 5 alpha, with IC50 values of 1.0 +/- 0.4 mu M and 1.6 +/- 1.4 mu M, 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 K-d values were estimated to be 0.3 mu M against (RS)-3, 5-dihydroxyphenylglycine-induced depolarisation and 0.5 mu M against (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid-induced depolarisation, respectively. On the other hand, the dorsal root-ventral root potential elicited at 8x threshold was depressed by LY393053 with IC50 values of 9.0 +/- 0.7 mu M and 12.7 +/- 1.7 mu M 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. (C) 1999 IBRO. Published by Elsevier Science Ltd.