PT  - JOURNAL ARTICLE
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
TI  - 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
AID  - 10.1124/jpet.107.127258
DP  - 2007 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 665--674
VI  - 323
IP  - 2
4099  - http://jpet.aspetjournals.org/content/323/2/665.short
4100  - http://jpet.aspetjournals.org/content/323/2/665.full
SO  - J Pharmacol Exp Ther2007 Nov 01; 323
AB  - 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