A Molecular Reactivity Template for Cannabinoid Activity
Chemistry and Biochemistry
Methods of theoretical chemistry are used to characterize the molecular structure and some reactivity properties of the major psychopharmacologically active component of cannabis, (—)-trans-Δ9-tetrahydrocannabinol (Δ9-THC). This characterization is part of an exploration of the molecular parameters that could serve to unify considerations of structure-activity relationships in disparate classes of cannabinoids. Our hypothesis is that there are two components of the Δ9-THC structure that confer upon the molecule reactivity characteristics crucial to activity: the lone pairs of electrons of the phenol oxygen, and the orientation of the carbocyclic ring. The conformation of Δ9-THC is calculated using molecular mechanics. Since the position of the phenolic OH is central to the working hypothesis, the rotational energy behavior of the phenolic OH is studied. Results from the calculations identify two minimum energy conformations of the OH in Δ9-THC. Results from ab-initio calculations of the OH rotation on a model fragment of Δ9-THC agree well with the molecular mechanics results. The molecular electrostatic potential (MEP) of Δ9-THC is calculated for the energetically optimal conformations. The results indicate that the two faces of the Δ9-THC molecule are distinguishable. The MEP of the bottom face of Δ9-THC (in each of the two minimum energy conformations of the phenolic OH), along with the conformational results for the orientation of the carbocyclic ring relative to the phenol group form a reactivity template to be used in comparisons with properties of active and inactive cannabinoids.