Department of Chemistry, Merck Research Laboratories, MSD Ltd, Newhouse, Lanarkshire, UK.
Bioorg Med Chem Lett. 2010 Dec 15;20(24):7327-30. doi: 10.1016/j.bmcl.2010.10.061. Epub 2010 Oct 20.
Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
双环哌嗪衍生物被合成作为 N-烷基哌嗪的构象限制类似物，并被发现是有效的 CB1 受体激动剂。CB1 受体激动剂活性取决于双环环系统手性中心的绝对构型。尽管构象限制不能防止化合物被 N-脱烷基化代谢，但发现几种双环类似物比无约束的先导化合物更有效。化合物 8b 在体内表现出有效的镇痛活性。
