K-685, a TRPV1 Antagonist, Blocks PKC-Sensitized TRPV1 Activation and Improves the Inflammatory Pain in a Rat Complete Freund’s Adjuvant Model

Journal of Pharmacological Sciences

Atsushi Inayoshi¹  Osamu Saku²  Kazuaki Inoue¹  Yozo Kojima¹  Hiroko Miura-Kusaka¹  Shin-ichiro Toki¹  Yoshiyuki Sugimoto¹  Shiro Shirakura¹  Katsumi Shinoda¹  Hiroshi Ishida²  Kiyotoshi Mori¹  Nobuyuki Suzuki¹  Eri Atsumi²  Yoshisuke Nakasato² 

[1] Drug Discovery Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., Japan;Medicinal Chemistry Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., Japan

关键词: TRPV1 antagonist;    pain;    protein kinase C (PKC);    inflammation;    complete Freund’s adjuvant (CFA);   

DOI  :  10.1254/jphs.13088FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(32)Cited-By(3)Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+-permeable non-selective cation channel that transmits pain signals. TRPV1 is activated by multiple stimuli such as capsaicin, acid, and heat. During inflammation, TRPV1 is reported to be sensitized by protein kinase C (PKC) in dorsal root ganglia (DRG) neurons, which leads to reduction in the threshold of the temperature for TRPV1 activation to body temperature. This sensitization is considered to contribute to chronic inflammatory pain. In a previous study, we discovered orally active 5,5-diarylpentadienamide TRPV1 antagonists. To examine the effects of our TRPV1 antagonists on PKC-sensitized TRPV1, we developed an in vitro assay system to monitor the TRPV1 sensitization by PKC. In this assay system, our TRPV1 antagonists, such as (2E,4Z)-N-[(3R)-3-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolyl]-5-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenyl)-2,4-pentadienamide (K-685), inhibited the activation of TRPV1 sensitized by PKC. The potentiation of heat-induced inward currents by PKC was seen in rat DRG neurons, and K-685 attenuated these currents. Furthermore, K-685 reversed the thermal hyperalgesia and mechanical allodynia in a rat complete Freund’s adjuvant–induced inflammatory pain model. These results therefore suggest that K-685 has a strong potential as a new analgesic drug for the treatment of inflammatory pain.

【 授权许可】

Unknown