TY - JOUR T1 - Pharmacology and Antitussive Efficacy of 4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic Acid (5-Trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a Transient Receptor Potential Vanilloid 1 Antagonist in Guinea Pigs JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 665 LP - 674 DO - 10.1124/jpet.107.127258 VL - 323 IS - 2 AU - Anindya Bhattacharya AU - Brian P. Scott AU - Nadia Nasser AU - Hong Ao AU - Michael P. Maher AU - Adrienne E. Dubin AU - Devin M. Swanson AU - Nigel P. Shankley AU - Alan D. Wickenden AU - Sandra R. Chaplan Y1 - 2007/11/01 UR - http://jpet.aspetjournals.org/content/323/2/665.abstract N2 - Transient receptor potential vanilloid 1 (TRPV1) plays an integral role in modulating the cough reflex, and it is an attractive antitussive drug target. The purpose of this study was to characterize a TRPV1 antagonist, 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), against the guinea pig TRPV1 receptor in vitro followed by a proof-of-principle study in an acid-induced model of cough. The affinity of JNJ17203212 for the recombinant guinea pig TRPV1 receptor was estimated by radioligand binding, and it was functionally characterized by antagonism of low-pH and capsaicin-induced activation of the ion channel (fluorometric imaging plate reader and electrophysiology). The nature of antagonism was further tested against the native channel in isolated guinea pig tracheal rings. Following pharmacokinetic characterization of JNJ17203212 in guinea pigs, pharmacodynamic and efficacy studies were undertaken to establish the antitussive efficacy of the TRPV1 antagonist. The pKi of JNJ17203212 for recombinant guinea pig TRPV1 was 7.14 ± 0.06. JNJ17203212 inhibited both pH (pIC50 of 7.23 ± 0.05) and capsaicin (pIC50 of 6.32 ± 0.06)-induced channel activation. In whole-cell patch clamp, the pIC50 for inhibition of guinea pig TRPV1 was 7.3 ± 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea, with a pKB value of 6.2 ± 0.1. Intraperitoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 ± 0.4 μM, and it attenuated capsaicin evoked coughs with similar efficacy to codeine (25 mg/kg). Last, JNJ17203212 dose-dependently produced antitussive efficacy in citric acid-induced experimental cough in guinea pigs. Our data provide preclinical support for developing TRPV1 antagonists for the treatment of cough. The American Society for Pharmacology and Experimental Therapeutics ER -