Pharmacological characterization of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel transient receptor potential vanilloid 1 antagonist

• Published in: The Journal of pharmacology and experimental therapeutics 2012-08, Vol.342 (2), p.520-528
• Main Authors: Kitagawa, Yoshihiro, Miyai, Atsuko, Usui, Kenji, Hamada, Yuji, Deai, Katsuya, Wada, Masashi, Koga, Yoshihisa, Sakata, Masahiro, Hayashi, Mikio, Tominaga, Makoto, Matsushita, Mutsuyoshi
• Format: Article
• Language: English
• Subjects: Animals; Benzoxazines - pharmacology; Body Temperature - drug effects; Capsaicin - pharmacology; Carrageenan - pharmacology; Central Nervous System Stimulants - pharmacology; HEK293 Cells; Humans; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Male; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - metabolism
• ISSN: 1521-0103
• DOI: 10.1124/jpet.112.194027

Transient receptor potential vanilloid 1 (TRPV1) activation in peripheral sensory nerve is known to be associated with various pain-related diseases, thus TRPV1 has been the focus as a target for drug discovery. In this study, we characterized the pharmacological profiles of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel TRPV1 antagonist. JTS-653 displaced [(3)H]resiniferatoxin binding to human and rat TRPV1. JTS-653 competitively antagonized the capsaicin-induced activation of human TRPV1 with pA(2) values of 10.1. JTS-653 also inhibited proton-induced activation of human and rat TRPV1 with IC(50) values of 0.320 and 0.347 nM, respectively. Electrophysiological studies indicated that JTS-653 blocked heat-induced inward currents in rat TRPV1 with IC(50) values of 1.4 nM. JTS-653 showed weak or no inhibitory effects on other TRP channels, receptors, and enzymes. JTS-653 significantly prevented capsaicin-induced mechanical hyperalgesia at 1 mg/kg p.o. and attenuated carrageenan-induced mechanical hyperalgesia at 0.3 mg/kg p.o. JTS-653 significantly attenuated carrageenan-induced thermal hyperalgesia at 0.1 mg/kg p.o. and fully reversed at 0.3 mg/kg p.o. without affecting the volume of the carrageenan-treated paw. JTS-653 showed a transient increase of body temperature at 0.3 mg/kg p.o. These results indicated that JTS-653 is a highly potent and selective TRPV1 antagonist in vitro and in vivo and suggested that JTS-653 is one of the most potent TRPV1 antagonists. The profiles of JTS-653, high potency in vivo and transient hyperthermia, seem to be associated with polymodal inhibition of TRPV1 activation.