title: K-685, a TRPV1 antagonist, blocks PKC-sensitized TRPV1 activation and improves the inflammatory pain in a rat complete Freund's adjuvant model.
abstract: Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-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.
authors.affiliation: Drug Discovery Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Yozo
authors.initials: Y
authors.lastname: Kojima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inayoshi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Inoue
authors.forename: Hiroko
authors.initials: H
authors.lastname: Miura-Kusaka
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Osamu
authors.initials: O
authors.lastname: Saku
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishida
authors.forename: Eri
authors.initials: E
authors.lastname: Atsumi
authors.forename: Yoshisuke
authors.initials: Y
authors.lastname: Nakasato
authors.forename: Shiro
authors.initials: S
authors.lastname: Shirakura
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Toki
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shinoda
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000700:Analgesics; D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000009:adverse effects*; D007249:Inflammation / Q000150:complications*; D008297:Male; D010421:Pentanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000502:physiology*; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000700:Analgesics; C000589262:N-(3-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolyl)-5-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenyl)-2,4-pentadienamide; D010421:Pentanoic Acids; D015363:Quinolones; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D005620:Freund's Adjuvant; D011493:Protein Kinase C