Characterization of a region of steric interference at the cannabinoid receptor using the active analog approach

In this paper, it is hypothesized that the distinction between certain active and inactive cannabinoids is that the inactive analogs possess extra volume associated with their carbocyclic rings that may be responsible for an unfavorable interaction at the cannabinoid receptor. Using the active analog approach, a model is developed of a region of steric interference at this receptor using the active cannabinoids (-)-trans-delta 9-tetrahydrocannabinol, (-)-trans-delta 8-tetrahydrocannabinol, (-)-11-hydroxy-beta-hexahydrocannabinol, and a (-)-trans-11-hydroxy-delta 8-tetrahydrocannabinol dimethylheptyl derivative and the inactive cannabinoids (9S,6aR)-trans-delta 10,10a-tetrahydrocannabinol and a (+)-trans-11-hydroxy-delta 8-tetrahydrocannabinol dimethylheptyl derivative. Each of these molecules satisfy the cannabinoid pharmacophoric requirements, i.e., a phenolic oxygen at C1 and a side chain of acceptable length at C3. Accessible conformers of each molecule were identified by using the method of molecular mechanics as encoded in the MMP2(85) program. The MAP facility within the Chem-X molecular modeling program was then used to calculate the region of steric interference (termed the receptor essential volume, REV) from these accessible conformers. The calculations revealed an REV region located near the top of the carbocyclic ring in the bottom face of the molecule. In order to explore the use of this REV to account for the activities of other cannabinoids, the minimally active classical cannabinoid (-)-11-hydroxy-alpha-hexahydrocannabinol, an active benzofuran cannabinoid, and the active nonclassical cannabinoid CP-47,497 were then studied. In each case, the activity or minimal activity of each compound can be explained on the basis of the ability of one or more accessible conformer of each molecule to clear the REV calculated here. The results of this study provide an explanation at the molecular level for observed activity differences between cannabinoids that exhibit shape differences associated with their carbocyclic rings.