THE DESIGN, SYNTHESIS AND TESTING OF DEOXY-CBD - FURTHER EVIDENCE FORA REGION OF STERIC INTERFERENCE AT THE CANNABINOID RECEPTOR

Cannabidiol CBD, a non-psychoactive constituent of marihuana, has been reported to possess essentially no affinity for cannabinoid CB1 recep tor binding sites in the brain. Our hypothesis concerning CBD's lack o f affinity for the cannabinoid CB1 receptor is that CBD is not capable of clearing a region of steric interference at the CB1 receptor and t hereby not able to bind to this receptor. We have previously character ized this region of steric interference at the CB1 receptor [P.H. Regg io, A.M. Panu, S. Miles J. Med. Chem. 36, 1761-1771 (1993)] in three d imensions using the Active Analog Approach. We report here a conformat ional analysis of CBD which, in turn, led to the design of a new analo g, desoxy-CBD. Modeling results for desoxy-CBD predict that this compo und is capable of clearing the region of steric interference by expend ing 3.64 kcal/mol of energy in contrast to the 12.39 kcal/mol expendit ure required by CBD. Desoxy-CBD was synthesized by condensation of 3-p entylphenol with p-mentha-2,8-dien-1-ol mediated by DMF-dineopental ac etal. Desoxy-CBD was found to behave as a partial agonist in the mouse vas deferens assay, an assay which is reported to detect the presence of cannabinoid receptors. The compound produced a concentration relat ed inhibition of electrically-evoked contractions of the mouse vas def erens, possessing an IC50 of 30.9 nM in this assay. Taken together, th ese results support the hypothesis of the existence of a region of ste ric interference at the CB1 receptor. While the energy expenditure to clear this region was too high for the parent compound, CBD, the remov al of the C6' hydroxyl of CBD produced a molecule (desoxy-CBD) able to clear this region and produce activity, albeit at a reduced level.