[Epub ahead of print]
Sharma R, Nikas SP, Paronis CA, Wood JT, Halikhedkar A, Guo JJ, Thakur GA, Kulkarni S, Benchama O, Raghav JG, Gifford RS, Jarbe TU, Bergman J, Makriyannis A.
We report an approach for obtaining novel cannabinoid analogs 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 (-)-D8-THC analogs. We have sought to introduce benzylic substituents alpha 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 analogs 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 analogs were shown to be potent CB1 receptor agonists and exhibit CB1-mediated hypothermic and analgesic effects.
- [PubMed – as supplied by publisher]