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Probing the carboxyester side chain in controlled deactivation (-)-δ(8)-tetrahydrocannabinols.

Abstract：

:We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (-)-Δ(8)-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain's polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Nikas SP,Sharma R,Paronis CA,Kulkarni S,Thakur GA,Hurst D,Wood JT,Gifford RS,Rajarshi G,Liu Y,Raghav JG,Guo JJ,Järbe TU,Reggio PH,Bergman J,Makriyannis A

doi

10.1021/jm501165d

subject

Has Abstract

pub_date

2015-01-22 00:00:00

pages

665-81

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

杂志文章

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