A Molecular Reactivity Template for Cannabinoid Analgesic Activity
The methods of theoretical chemistry were used to characterize the molecular structure and some reactivity properties of (–)-9-nor-9β-hydroxyhexahydrocannabinol (9-nor-9β-OH-HHC), our template molecule for cannabinoid analgesia. This characterization is part of a project whose ultimate goal is the design of cannabinoid analgesics with reduced psychoactive liabilities. Our working hypothesis is that the analgesic activity of 9-nor-9β-OH-HHC is due to the presence and relative location of two regions of negative potential in the top half of the molecule. A complete conformational study of the fused ring structure of 9-nor-9β-OH-HHC was performed using the technique of molecular mechanics as encoded in the MMP2(85) program. This study revealed six accessible conformers of 9-nor-9β-OH-HHC. All six conformers were found to have the same fused ring conformation, but to differ in the position of the phenol and 9β-hydroxyl groups. Molecular electrostatic potential (MEP) maps of each accessible conformer were calculated from molecular wave functions obtained with the LP-3G basis set implemented into the Gaussian 80 program. The MEP maps calculated at distances of 1.5 and 3.3 Å from the molecular plane defined by the aromatic ring serve as a discriminative factor for the conformers of the studied compound. In order to quantiate the spatial relationship of the potential minima in the MEPs of each accessible conformer, points of minimum potential associated with the 9β-hydroxyl oxygen (X1 at –1.5 Å and X2 at –3.3 Å) and with the phenol oxygen (Y1 at 1.5 Å and Y2 at –1.5 Å) were identified in the MEP maps of each conformer. The distances, |;XnYn|, and the nonbonded torsion angles, Yn–O–C9–Xn, were then measured for all conformers. The accessible conformations of 9-nor-9β-OH-HHC along with their MEPs and the measurements |XnYn| and Yn–O–C9–Xn form our preliminary template for cannabinoid analgesia. Future comparisons of this template with the properties of active and inactive cannabinoid analgesics should permit the identification of the relevant conformer at the site of action of these compounds and permit the formulation of an interaction site model for the cannabinoid analgesics.
Reggio PH, Frecer V, Mazurek AP. 1990. A molecular reactivity template for cannabinoid analgesic activity. International Journal of Quantum Chemistry 38(S17):119-31.