Regulating AMPA Receptors with Isoxazole-4-Carboxamide Derivatives: An Electrophysiological Study
Publication Type
Original research
Authors

Isoxazole carboxamide derivatives are intriguing modulators of ionotropic glutamate receptors; more specifically, their prospective analgesic activities based on non-opioid pathways have sparked widespread research. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, especially Ca2+-permeable subtypes that are highly expressed in the spinal dorsal horn, play a critical role in nociceptive transmission and inflammatory pain. Herein, the neuromodulatory effects of these derivatives on AMPA receptor activity have been studied, focusing on their potential as modulators of AMPA receptors, a target implicated in pain and neurological disorders. The whole-cell patch clamp technique for electrophysiological recordings was used to investigate the effect of twelve isoxazole-4-carboxamide derivatives (CIC-1-12) on AMPA receptors’ whole-cell currents and kinetics, including deactivation and desensitization. The isoxazole-4-carboxamide derivatives tested as inhibitors of AMPA receptor activity were very potent, with an 8-fold inhibition by CIC-1 and a 7.8-fold reduction by CIC-2. Additionally, these compounds profoundly altered the biophysical gating properties of both homomeric and heteromeric receptor subunits. These findings emphasize the therapeutic promise of isoxazole-4-carboxamide derivatives due to their potential as AMPA receptor modulators. Their ability to affect receptor activity and gating properties makes them promising candidates for future treatments for controlling pain.

Journal
Title
Journal of Xenobiotics
Publisher
MDPI
Publisher Country
Switzerland
Indexing
Thomson Reuters
Impact Factor
6.8
Publication Type
Online only
Volume
15
Year
2025
Pages
40