RT Journal Article
SR Electronic
T1 Pharmacological Characterization of (3<em>S</em>)-3-(Hydroxymethyl)-4-(5-Methylpyridin-2-yl)-<em>N</em>-[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]-3,4-Dihydro-2<em>H</em>-Benzo[<em>b</em>][1,4]Oxazine-8-Carboxamide (JTS-653), a Novel Transient Receptor Potential Vanilloid 1 Antagonist
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 520
OP 528
DO 10.1124/jpet.112.194027
VO 342
IS 2
A1 Yoshihiro Kitagawa
A1 Atsuko Miyai
A1 Kenji Usui
A1 Yuji Hamada
A1 Katsuya Deai
A1 Masashi Wada
A1 Yoshihisa Koga
A1 Masahiro Sakata
A1 Mikio Hayashi
A1 Makoto Tominaga
A1 Mutsuyoshi Matsushita
YR 2012
UL http://jpet.aspetjournals.org/content/342/2/520.abstract
AB 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 [3H]resiniferatoxin binding to human and rat TRPV1. JTS-653 competitively antagonized the capsaicin-induced activation of human TRPV1 with pA2 values of 10.1. JTS-653 also inhibited proton-induced activation of human and rat TRPV1 with IC50 values of 0.320 and 0.347 nM, respectively. Electrophysiological studies indicated that JTS-653 blocked heat-induced inward currents in rat TRPV1 with IC50 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.