Abstract
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 +/- 0.06. JNJ17203212 inhibited both pH (pIC(50) of 7.23 +/- 0.05) and capsaicin (pIC(50) of 6.32 +/- 0.06)-induced channel activation. In whole-cell patch clamp, the pIC(50) for inhibition of guinea pig TRPV1 was 7.3 +/- 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea, with a pK(B) value of 6.2 +/- 0.1. Intraperitoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 +/- 0.4 microM, 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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Pharmacology and Experimental Therapeutics
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
