TY - JOUR T1 - Amelioration of neuropathic pain by novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in rats without hyperthermic effect. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.110.175570 SP - jpet.110.175570 AU - Tomonari Watabiki AU - Tetsuo Kiso AU - Takahiro Kuramochi AU - Koichi Yonezawa AU - Noriko Tsuji AU - Atsuyuki Kohara AU - Shuichiro Kakimoto AU - Toshiaki Aoki AU - Nobuya Matsuoka Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/11/22/jpet.110.175570.abstract N2 - Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal pain models; however, some compounds induce hyperthermia in animals and humans. We discovered the novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in our laboratory. AS1928370 bound to the resiniferatoxin binding site on TRPV1 and inhibited capsaicin-mediated inward currents with an IC50 value of 32.5 nM. Although AS1928370 inhibited the capsaicin-induced Ca2+ flux in human and rat TRPV1-expressing cells, the inhibitory effect on proton-induced Ca2+ flux was extremely small. In addition, AS1928730 showed no inhibitory effects on TRPV4, TRPA1, and TRPM8 up to 10 μM. AS1928370 improved capsaicin-induced secondary hyperalgesia and mechanical allodynia in an L5/L6 spinal nerve ligation model in rats with respective ED50 values of 0.17 and 0.26 mg/kg (p.o.). Further, AS1928370 alleviated inflammatory pain in a complete Freund's adjuvant model at 10 mg/kg (p.o.). AS1928370 had no effect on rectal body temperature up to 10 mg/kg (p.o.), although a significant hypothermic effect was noted at 30 mg/kg (p.o.). In addition, AS1928370 showed no significant effect on motor coordination. These results suggest that blockage of TRPV1 receptor without affecting the proton-mediated TRPV1 activation is a promising approach to treating neuropathic pain due to the potential wide safety margin against hyperthermic effects. As such, compounds such as ASP1928370 may have potential as new analgesic agents for treating neuropathic pain. ER -