title: Design, synthesis and biological evaluation of novel analgesic agents targeting both cyclooxygenase and TRPV1.
abstract: Multitarget-directed ligands might offer certain advantages over traditional single-target drugs and/or drug combinations. In the present study, a series of novel analgesic agents targeting both cyclooxygenase and TRPV1 were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazine, ethanediamine cores. These compounds were evaluated for antagonism of hTRPV1 activation by capsaicin and the ability to inhibit Ovine COX-1 and human recombinant COX-2 in vitro. The favorable potentials of these test compounds were further characterized in preliminary analgesic and side-effects tests in vivo. On the basis of comprehensive evaluations, compound 8d which showed strong TRPV1 antagonistic activity, middle COX-2 inhibition, weak ulcerogenic action and had no hyperthermia side-effect was considered as a safe candidate for the further development of analgesic drugs.
authors.affiliation: Institute of Chemistry & Biology, Henan University, Kaifeng 475004, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Miaobo
authors.initials: M
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Mian
authors.initials: M
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; WuXiAppTec (Wuhan) Co., Ltd, Wuhan 430000, China.
authors.forename: Jingjie
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: ydhuangwenlong@126.com.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: qianhai24@163.com.
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
mesh_terms: D019342:Acetic Acid; D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature; D002211:Capsaicin / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003959:Diamines / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D015870:Gene Expression; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D008297:Male; D051379:Mice; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000700:Analgesics; D003959:Diamines; D010879:Piperazines; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019342:Acetic Acid; D002211:Capsaicin; D007052:Ibuprofen
keywords: Analgesic; Cyclooxygenase; Hyperthermia; Transient receptor potential vanilloid type 1