title: 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.
abstract: 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.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. yoshihiro.kitagawa@jt.com
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Atsuko
authors.initials: A
authors.lastname: Miyai
authors.forename: Kenji
authors.initials: K
authors.lastname: Usui
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hamada
authors.forename: Katsuya
authors.initials: K
authors.lastname: Deai
authors.forename: Masashi
authors.initials: M
authors.lastname: Wada
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Koga
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakata
authors.forename: Mikio
authors.initials: M
authors.lastname: Hayashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
authors.forename: Mutsuyoshi
authors.initials: M
authors.lastname: Matsushita
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D002351:Carrageenan / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C576953:3-(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; D048588:Benzoxazines; D000697:Central Nervous System Stimulants; D011725:Pyridines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002351:Carrageenan; D002211:Capsaicin