Synthesis and biological evaluation of aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists: a potential treatment for neuropathic pain.

Abstract

Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain. In this study, we have developed mGluR1 antagonists with an aryl isoxazole scaffold, and identify several compounds that are orally active in vivo. We believe that these compounds can serve as a useful tool for the investigation of the role of mGluR1 and a promising lead for the potential treatment of neuropathic pain.

• Authors: Gyeong Hi Cho, TaeHun Kim, Woo Seung Son, Seon Hee Seo, Sun-Joon Min, Yong Seo Cho, Gyochang Keum, Kyu-Sung Jeong, Hun Yeong Koh, Jiyoun Lee, Ae Nim Pae
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 6 Pg. 1324-8 (Mar 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 25677662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics
• Isoxazoles
• Receptors, Metabotropic Glutamate
• metabotropic glutamate receptor type 1

Topics

• Administration, Oral
• Analgesics (chemical synthesis, pharmacology, therapeutic use)
• Animals
• Disease Models, Animal
• Isoxazoles (chemistry, therapeutic use)
• Neuralgia (chemically induced, drug therapy)
• Protein Binding
• Rats
• Receptors, Metabotropic Glutamate (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship