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J Med Chem. 2013 Dec 27;56(24):10142-57. doi: 10.1021/jm4016075. Epub 2013 Dec 10.

Controlled-deactivation cannabinergic ligands.

Author information

1
Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.

Abstract

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.

PMID:
24286207
PMCID:
PMC3905450
DOI:
10.1021/jm4016075
[Indexed for MEDLINE]
Free PMC Article

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