title: Synthesis of Analogues of BCTC Incorporating a Pyrrolidinyl Linker and Biological Evaluation as Transient Receptor Potential Vanilloid 1 Antagonists.
abstract: A series of novel pyrrolidinyl linker TRPV1 antagonists were prepared in an effort to lower the hyperthermic side-effects of first-generation antagonist BCTC. These compounds were investigated for antagonism of hTRPV1 activation by capsaicin and acid in vitro. Preliminary results suggested the compounds 10a, 10b, 10c and 10j had favorable TRPV1 antagonism activity. In further studies in vivo, 10b, comparable to BCTC, showed potent analgesic activity in capsaicin-induced and heat-induced pain models. In addition, 10b indicated a reduced risk of body temperature elevation. All of these demonstrated that 10b can be 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: 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.
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: Qianqian
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
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.
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002211:Capsaicin / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013696:Temperature
chemical_list: D000577:Amides; D000700:Analgesics; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C494484:TRPV1 receptor; D002211:Capsaicin
keywords: BCTC; analgesic; hyperthermia; transient receptor potential vanilloid type 1