title: Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues.
abstract: In pursuit of safer controlled-deactivation cannabinoids with high potency and short duration of action, we report the design, synthesis, and pharmacological evaluation of novel C9- and C11-hydroxy-substituted hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues in which a seven atom long side chain, with or without 1'-substituents, carries a metabolically labile 2',3'-ester group. Importantly, in vivo studies validated our controlled deactivation approach in rodents and non-human primates. The lead molecule identified here, namely, butyl-2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-2-methylpropanoate (AM7499), was found to exhibit remarkably high in vitro and in vivo potency with shorter duration of action than the currently existing classical cannabinoid agonists.
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Shashank
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Spyros P
authors.initials: SP
authors.lastname: Nikas
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Rishi
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.|McLean Hospital, and Harvard Medical School, Belmont, Massachusetts 02478, United States.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Paronis
authors.affiliation: McLean Hospital, and Harvard Medical School, Belmont, Massachusetts 02478, United States.
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Leonard
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Honrao
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Srikrishnan
authors.initials: S
authors.lastname: Mallipeddi
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Jimit Girish
authors.initials: JG
authors.lastname: Raghav
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Othman
authors.initials: O
authors.lastname: Benchama
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.
authors.forename: Torbjörn U C
authors.initials: TU
authors.lastname: Järbe
authors.affiliation: McLean Hospital, and Harvard Medical School, Belmont, Massachusetts 02478, United States.
authors.forename: Jack
authors.initials: J
authors.lastname: Bergman
authors.affiliation: Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.|King Abdulaziz University , Jeddah, 22254, Saudi Arabia.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002187:Cannabinol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D012453:Saimiri; D013329:Structure-Activity Relationship
chemical_list: D063386:Cannabinoid Receptor Agonists; D043882:Receptors, Cannabinoid; D002187:Cannabinol