Natural-Product-Derived Transient Receptor Potential Melastatin 8 (TRPM8) Channel Modulators

Authors

Christina M. Legay, University of Calgary
Evgueni Gorobets, University of Calgary
Mircea Iftinca, University of Calgary
Rithwik Ramachandran, Western University
Christophe Altier, University of Calgary
Darren J. Derksen, University of Calgary

Document Type

Article

Publication Date

6-3-2016

Journal

Organic Letters

Volume

18

Issue

11

First Page

2746

Last Page

2749

URL with Digital Object Identifier

10.1021/acs.orglett.6b01222

Abstract

© 2016 American Chemical Society. A library of novel structural hybrids of menthol and cubebol was tested for each derivative's ability to interact with the transient receptor potential subfamily melastatin member 8 (TRPM8) channel. This structure-activity relationship study revealed three potent modulators of the TRPM8 ion channel: a novel agonist (4) with an EC50 value of 11 ± 1 μM, an antagonist (15) with an IC50 value of 2 ± 1 μM, and an allosteric modulator (21) that minimized channel desensitization toward menthol. Each of these novel exocyclic olefin analogues of menthol is readily accessible by synthesis and was tested using Ca2+ assays and electrophysiology.