title: Unsaturated side chain beta-11-hydroxyhexahydrocannabinol analogs.
abstract: The cannabinoid side chain is a key pharmacophore in the interaction of cannabinoids with their receptors (CB1 and CB2). To study the stereochemical requirements of the side chain, we synthesized a series of cannabinoids in which rotation around the C1'-C2' bond is blocked. The key steps in the synthesis were the cuprate addition of a substituted resorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the dihydropyran ring, and the stereospecific introduction of the beta-11-hydroxymethyl group. All the analogs tested showed nanomolar affinity for the receptors, the cis-hept-1-ene side chain having the highest affinity for CB1 (Ki = 0.89 nM) and showing the widest separation between CB1 and CB2 affinities. The parent n-heptyl-beta-11-hydroxyhexahydrocannabinol was the least potent binding to CB1 (Ki = 8.9 nM) and had the lowest selectivity between CB1 and CB2.
authors.affiliation: Department of Chemistry, University of Hawaii, Honolulu 96822, USA.
authors.forename: J
authors.initials: J
authors.lastname: Busch-Petersen
authors.forename: W A
authors.initials: WA
authors.lastname: Hill
authors.forename: P
authors.initials: P
authors.lastname: Fan
authors.forename: A
authors.initials: A
authors.lastname: Khanolkar
authors.forename: X Q
authors.initials: XQ
authors.lastname: Xie
authors.forename: M A
authors.initials: MA
authors.lastname: Tius
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000737:chemistry*; D002462:Cell Membrane / Q000378:metabolism; D003198:Computer Simulation; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D016548:Prosencephalon / Q000378:metabolism; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
chemical_list: C101615:11-hydroxyhexahydrocannabinol; C101616:3-(1-heptenyl)-hexahydro-9-hydroxymethyl-6,6-dimethyl-6H-dibenzo(b,d)pyran-1-ol; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol