Isoxazole carboxamide derivatives are intriguing modulators of ionotropic glutamate
receptors; more specifically, their prospective analgesic activities based on nonopioid
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 wholecell
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.

Title

Journal of Xenobiotics

Publisher

Multidisciplinary Digital Publishing Institute (MDPI)

Publisher Country

Switzerland

Indexing

Thomson Reuters

Impact Factor

4.4

Publication Type

Online only

Volume

15

Year

2025

Pages

1-19