title: 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.
authors.affiliation: Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.forename: Rishi
authors.initials: R
authors.lastname: Sharma
authors.forename: Carol A
authors.initials: CA
authors.lastname: Paronis
authors.forename: Shashank
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Ganesh A
authors.initials: GA
authors.lastname: Thakur
authors.forename: Dow
authors.initials: D
authors.lastname: Hurst
authors.forename: JodiAnne T
authors.initials: JT
authors.lastname: Wood
authors.forename: Roger S
authors.initials: RS
authors.lastname: Gifford
authors.forename: Girija
authors.initials: G
authors.lastname: Rajarshi
authors.forename: Yingpeng
authors.initials: Y
authors.lastname: Liu
authors.forename: Jimit Girish
authors.initials: JG
authors.lastname: Raghav
authors.forename: Jason Jianxin
authors.initials: JJ
authors.lastname: Guo
authors.forename: Torbjörn U C
authors.initials: TU
authors.lastname: Järbe
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.forename: Jack
authors.initials: J
authors.lastname: Bergman
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol