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: Y Chen, G Bacon, E Sher, B P Clark, M J Kallman, R A Wright, B G Johnson, D D Schoepp, A E Kingston
• Journal: Neuroscience (Neuroscience) Vol. 95 Issue 3 Pg. 787-93 ( 2000) ISSN: 0306-4522 [Print] United States
• PMID: 10670446 (Publication Type: Journal Article)

Chemical References

• Excitatory Amino Acid Antagonists
• LY393053
• Neuroprotective Agents
• Propionates
• Receptors, Metabotropic Glutamate
• Resorcinols
• Cycloleucine
• 1-amino-1,3-dicarboxycyclopentane
• 3,5-dihydroxyphenylglycine
• Acetic Acid
• Glycine

Topics

• Acetic Acid
• Animals
• Animals, Newborn (physiology)
• Cycloleucine (analogs & derivatives, pharmacology)
• Electrophysiology
• Excitatory Amino Acid Antagonists (pharmacology)
• Glycine (analogs & derivatives, pharmacology)
• In Vitro Techniques
• Mice
• Motor Neurons (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Nociceptors (drug effects)
• Pain (chemically induced, physiopathology)
• Propionates (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Metabotropic Glutamate (antagonists & inhibitors)
• Resorcinols (pharmacology)
• Spinal Cord (physiopathology)
• Spinal Nerve Roots (drug effects, physiology)
• Stereoisomerism