부산대학교 도서관

The transient receptor potential melastatin type 8 (TRPM8)is anonselective cation channel primarily expressed in a subpopulationof 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 approachfor the treatment of pain. As a result of our screening efforts, weidentified tetrahydrothienopyridine 4as an inhibitorof icilin-induced calcium influx in CHO cells expressing recombinantrat TRPM8. Exploration of the structure–activity relationshipsof 4led to the identification of a potent and orallybioavailable TRPM8 antagonist, tetrahydroisoquinoline 87. Compound 87demonstrated target coverage in vivo afteroral administration in a rat pharmacodynamic model measuring the preventionof icilin-induced wet-dog shakes (WDS). [ABSTRACT FROM AUTHOR]