Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
J Med Chem. 2013 Dec 27;56(24):10142-57. doi: 10.1021/jm4016075. Epub 2013 Dec 10.
We report an approach for obtaining novel cannabinoid analogues with controllable deactivation and improved druggability. Our design involves the incorporation of a metabolically labile ester group at the 2'-position on a series of (-)-Δ(8)-THC analogues. We have sought to introduce benzylic substituents α to the ester group which affect the half-lives of deactivation through enzymatic activity while enhancing the affinities and efficacies of individual ligands for the CB1 and CB2 receptors. The 1'-(S)-methyl, 1'-gem-dimethyl, and 1'-cyclobutyl analogues exhibit remarkably high affinities for both CB receptors. The novel ligands are susceptible to enzymatic hydrolysis by plasma esterases in a controllable manner, while their metabolites are inactive at the CB receptors. In further in vitro and in vivo experiments key analogues were shown to be potent CB1 receptor agonists and to exhibit CB1-mediated hypothermic and analgesic effects.
我们报告了一种获得新型可控失活和改善成药性的大麻素类似物的方法。我们的设计涉及在一系列 (-)-Δ(8)-THC 类似物的 2'-位上引入代谢不稳定的酯基。我们试图在酯基的 α 位引入苄基取代基，这些取代基通过酶活性影响失活的半衰期，同时提高单个配体对 CB1 和 CB2 受体的亲和力和效力。1'-(S)-甲基、1'-双甲基和 1'-环丁基类似物对两个 CB 受体均表现出极高的亲和力。新型配体可通过血浆酯酶以可控的方式进行酶水解，而其代谢物对 CB 受体无活性。在进一步的体外和体内实验中，关键类似物被证明是有效的 CB1 受体激动剂，并表现出 CB1 介导的降温作用和镇痛作用。
