An extensive theoretical study of the stereoisomers of tetrahydrocannabinols has been performed at the ab initio HF/6-31G* and B3LYP/6-31G* levels. Effects of solvation were calculated with the Onsager model (with full geometry optimization), SCRF with Tomasi's PCM, and isodensity polarization continuum models. Single-point MP2//HF/6-31G* calculations were carried out. Frequency calculations for all the isomers at the HF/6-31G* level and for two natural isomers delta1-THC-RR and delta6-THC-RR at the B3LYP/6-31G* level were performed. Our results support the findings of the previous AM1 studies that the orientation of the carbocyclic ring and its C1 substituent with respect to the phenyl group hydroxyl oxygen play the major role in the activity. The calculated values of the LUMO energy (lowest unoccupied molecular orbital) and the hardness of the stereoisomers show that for the trans isomers it is easier to remove one electron from its HOMO (highest occupied molecular orbital) to the LUMO and easier to accept an electron from the receptor binding site than for the cis isomers. Combining geometric features (the orientation of the carbocyclic ring and its C1 substituent with respect to the phenyl group hydroxyl oxygen) with electronic features (LUMO and hardness), we explain the activity differences among the stereoisomers.
Computer Simulation Dronabinol