616226-82-5Relevant articles and documents
Fused piperidines as a novel class of potent and orally available transient receptor potential melastatin type 8 (TRPM8) antagonists
Tamayo, Nuria A.,Bo, Yunxin,Gore, Vijay,Ma, Vu,Nishimura, Nobuko,Tang, Phi,Deng, Hong,Klionsky, Lana,Lehto, Sonya G.,Wang, Weiya,Youngblood, Brad,Chen, Jiyun,Correll, Tiffany L.,Bartberger, Michael D.,Gavva, Narender R.,Norman, Mark H.
experimental part, p. 1593 - 1611 (2012/04/17)
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).
