Yan Lin, Wang Jingjie, Pan Miaobo, Qiu Qianqian, Huang Wenlong, Qian Hai
Institute of Chemistry & Biology, Henan University, Kaifeng, 475004, China.
State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
Chem Biol Drug Des. 2016 Feb;87(2):306-11. doi: 10.1111/cbdd.12661. Epub 2015 Oct 5.
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.
为了降低第一代拮抗剂BCTC的体温过高副作用，制备了一系列新型吡咯烷基连接的TRPV1拮抗剂。对这些化合物在体外拮抗辣椒素和酸激活hTRPV1的作用进行了研究。初步结果表明，化合物10a、10b、10c和10j具有良好的TRPV1拮抗活性。在进一步的体内研究中，与BCTC相当的10b在辣椒素诱导和热诱导的疼痛模型中显示出强效镇痛活性。此外，10b表明体温升高的风险降低。所有这些都表明，10b可被视为镇痛药进一步开发的安全候选药物。
