UNSATURATED SIDE-CHAIN BETA-11-HYDROXYHEXAHYDROCANNABINOL ANALOGS

The cannabinoid side chain is a key pharmacophore in the interaction o f cannabinoids with their receptors (CB1 and CB2), To study the stereo chemical requirements of the side chain, we synthesized a series of ca nnabinoids in which rotation around the C1'-C2' bond is blocked, The k ey steps in the synthesis were the cuprate addition of a substituted r esorcinol to (+)-apoverbenone, the TMSOTf-mediated formation of the di hydropyran ring, and the stereospecific introduction of the beta-11-hy droxymethyl group, All the analogs tested showed nanomolar affinity fo r the receptors, the cis-hept-1-ene side chain having the highest affi nity for CB1 (K-i = 0.89 nM) and skewing the widest separation between CB1 and CB2 affinities, The parent n-heptyl-beta-11-hydroxyhexahydroc annabinol was the least potent binding to CB1 (K-i = 8.9 nM) and had t he lowest selectivity between CB1 and CB2.