Isoxazole derivatives as potent transient receptor potential melastatin type 8 (TRPM8) agonists
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- 作者：Carmine Ostacolo ; Paolo Ambrosino ; Roberto Russo ; Matteo Lo Monte ; Maria Virginia Soldovieri ; Sonia Laneri ; Antonia Sacchi ; Giulio Vistoli ; Maurizio Taglialatela ; Antonio Calignano
- 关键词：Transient receptor potential melastatin type-8 channels ; Isoxazolylamine derivatives ; Structure&ndash ; activity relationship ; Calcium imaging ; Chronic constriction injury
- 刊名：European Journal of Medicinal Chemistry
- 出版年：November, 2013
- 年：2013
- 卷：69
- 期：Complete
- 页码：659-669
- 全文大小：1424 K
文摘
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聽vitro, and in an in聽vivo model of cold allodynia. In F11 sensory neurons, single-cell Ca2+-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聽min) but not later (7-9 or 14-16聽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 鈥渕enthol-like鈥?compounds (characterized by high efficacy/low potency), and 鈥渋cillin-like鈥?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.