Characterization of a Region of Steric Interference at the Cannabinoid Receptor Using the Active Analog Approach


Chemistry and Biochemistry

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In this paper, it is hypothesized that the distinction between certain active and inactive cannabinoids is that inactive analogs posses extra vol. assocd. 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-9-tetrahydrocannabinol (I), (-)-trans-Δ8-tetrahydrocannabinol (II; R = Me), (-)-11-hydroxy-β-hexahydrocannabinol (III), (-)-trans-1',1'-dimethyl-5'-ethyl-11-hydroxy-Δ8-tetrahydrocannabiniol (II; R = CH2OH), and the inactive cannabinoids (9S,6aR)-trans-Δ10,10a-tetrahydrocannabinol (IV), and (+)-trans-1',1'-dimethyl-5'-ethyl-11-hydroxy-Δ8-tetrahydrocannabinol (V). Each of these mols. satisfy the cannabinoid pharmacophoric requirements, i.e., a phenolic oxygen at C(1) and a side chain of acceptable length at C(3). Accessible conformers of each mol. were identified by using the method of mol. mechanics as encoded in the MMP2(85) program. The MAP facility within the CHEM-X mol. modeling program was then used to calc. the region of steric interference (termed the receptor essential vol., REV) from these accessible conformers. The calcns. revealed an REV region located near the top of the carbocyclic ring in the bottom face of the mol. In order to explore the use of this REV to account for the activities of other cannabinoids, the minimally active classical cannabinoid (-)-11-hydroxy-α-hexahydrocannabinol (9-epi-III), active benzofuran cannabinoid VI, and the active nonclassical cannabinoid CP-47,497, 3β-[2-hydroxy-4-(1,1-mimethylheptyl)phenyl]cyclohexan-1β-ol, were then studied. In each case, the activity or minimal activity of each compd. can be explained on the basis of the ability of one or more accessible conformer of each mol. to clear the REV calcd. here. The results of this study provide an explanation at the mol. level for obsd. activity differences between cannabinoids that exhibit shape differences assocd. with their carbocyclic rings.