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 pK i of JNJ17203212 for recombinant guinea pig TRPV1 was 7.14 Ϯ 0.06. JNJ17203212 inhibited both pH (pIC 50 of 7.23 Ϯ 0.05) and capsaicin (pIC 50 of 6.32 Ϯ 0.06)-induced channel activation. In whole-cell patch clamp, the pIC 50 for inhibition of guinea pig TRPV1 was 7.3 Ϯ 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea, with a pK B value of 6.2 Ϯ 0.1. Intraperitoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 Ϯ 0.4 M, 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 transient receptor potential vanilloid 1 (TRPV1 or VR1) receptor is a ligand-gated cation channel that is activated or modulated by a variety of mediators thought to contribute to neuroinflammation (Tominaga and Tominaga, 2005;Szallasi et al., 2007). This ion channel is a polymodal nociceptor that is activated by vanilloids such as capsaicin (Caterina et al., 1997), noxious heat (Cesare et al., 1999), low pH, polyamines (Ahern et al., 2006), and lipid mediators such as anandamide (Ross, 2003;De Petrocellis and Di Marzo, 2005), to mention a few. In addition, various endogenous mediators such as bradykinin, substance P, glutamate, prostaglandins, and ATP sensitize TRPV1 (Szallasi et al., 2007). As an integrator and mediator of nociceptive and/or inflammatory stimuli, TRPV1 is an attractive therapeutic target for the treatment of various neuroinflammatory disorders (Jia et Article, publication date, and citation information can be found at