Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM8

Title: Isoxazole derivatives as potent transient receptor potential melastatin type 8 (TRPM8) agonists.

Authors: Carmine Ostacolo, Paolo Ambrosino, Roberto Russo, Matteo Lo Monte, Maria Virginia Soldovieri, Sonia Laneri, Antonia Sacchi, Giulio Vistoli, Maurizio Taglialatela, Antonio Calignano

Journal, date & volume: Eur J Med Chem, 2013 Nov , 69, 659-69

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24095758

Abstract
Modulation of the transient receptor potential melastatin type-8 (TRPM8), the receptor for menthol acting as the major sensor for peripheral innocuous cool temperatures, has several important applications in pharmaceutical, food and cosmetic industries. In the present study, we designed 12 isoxazole derivatives and tested their pharmacological properties both in F11 sensory neurons in vitro, and in an in vivo model of cold allodynia. In F11 sensory neurons, single-cell Ca(2+)-imaging experiments revealed that, when compared to menthol, some newly-synthesized compounds were up to 200-fold more potent, though none of them showed an increased efficacy. Some isoxazole derivatives potentiated allodynic responses elicited by acetone when administered to rats subjected to sciatic nerve ligation; when compared to menthol, these compounds were efficacious at earlier (0-2 min) but not later (7-9 or 14-16 min) time points. Docking experiments performed in a human TRPM8 receptor model revealed that newly-synthesized compounds might adopt two possible conformations, thereby allowing to distinguish "menthol-like" compounds (characterized by high efficacy/low potency), and "icillin-like" compounds (with high potency/low efficacy). Collectively, these data provide rationale structure-activity relationships for isoxazole derivatives acting as TRPM8 agonists, and suggest their potential usefulness for cold-evoked analgesia.