Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM8

Title: Fused piperidines as a novel class of potent and orally available transient receptor potential melastatin type 8 (TRPM8) antagonists.

Authors: Nuria A Tamayo, Yunxin Bo, Vijay Gore, Vu Ma, Nobuko Nishimura, Phi Tang, Hong Deng, Lana Klionsky, Sonya G Lehto, Weiya Wang, Brad Youngblood, Jiyun Chen, Tiffany L Correll, Michael D Bartberger, Narender R Gavva, Mark H Norman

Journal, date & volume: J. Med. Chem., 2012 Feb 23 , 55, 1593-611

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22329507

Abstract
The transient receptor potential melastatin type 8 (TRPM8) is a nonselective cation channel primarily expressed in a subpopulation of sensory neurons that can be activated by a wide range of stimuli, including menthol, icilin, and cold temperatures (<25 °C). Antagonism of TRPM8 is currently under investigation as a new approach for the treatment of pain. As a result of our screening efforts, we identified tetrahydrothienopyridine 4 as an inhibitor of icilin-induced calcium influx in CHO cells expressing recombinant rat TRPM8. Exploration of the structure-activity relationships of 4 led to the identification of a potent and orally bioavailable TRPM8 antagonist, tetrahydroisoquinoline 87. Compound 87 demonstrated target coverage in vivo after oral administration in a rat pharmacodynamic model measuring the prevention of icilin-induced wet-dog shakes (WDS).