Unsaturated side chain beta-11-hydroxyhexahydrocannabinol analogs

J Med Chem. 1996 Sep 13;39(19):3790-6. doi: 10.1021/jm950934b.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cannabinoids / chemistry*
  • Cell Membrane / metabolism
  • Computer Simulation
  • Dronabinol / analogs & derivatives*
  • Dronabinol / chemistry
  • Dronabinol / metabolism
  • Mice
  • Models, Molecular
  • Prosencephalon / metabolism
  • Rats
  • Receptor, Cannabinoid, CB2*
  • Receptors, Cannabinoid
  • Receptors, Drug / metabolism*
  • Spleen / metabolism
  • Structure-Activity Relationship
  • Synaptosomes / metabolism


  • 11-hydroxyhexahydrocannabinol
  • 3-(1-heptenyl)-hexahydro-9-hydroxymethyl-6,6-dimethyl-6H-dibenzo(b,d)pyran-1-ol
  • Cannabinoids
  • Cnr2 protein, rat
  • Receptor, Cannabinoid, CB2
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Dronabinol