PHARMACOPHORIC REQUIREMENTS FOR CANNABINOID SIDE-CHAINS - MULTIPLE BOND AND C1'-SUBSTITUTED DELTA(8)-TETRAHYDROCANNABINOLS

Accumulated evidence indicates that within the cannabinoid structure t he aliphatic side chain plays a pivotal role in determining cannabimim etic activity. We describe the synthesis and affinities for the CB1 an d CB2 receptors of a series of novel Delta(8)-THC analogues in which t he side-chain pharmacophores are conformationally more defined than in the parent molecule. No analogue has the side-chain pharmacophore in a fully restricted conformation. However, our design serves to narrow down the scope of options for conformational requirements at the recep tor active sites. All the analogues tested showed nanomolar or subnano molar affinities for the receptors; 6,6,9-trimethyl-1-hydroxy-6H-diben zo[b,d]pyranyl)- 2-hexyl-1,3-dithiolane was found to possess very high affinity for both cannabinoid receptors(CB1, K-i = 0.32 nM; CB2, K-i = 0.52 nM).