2-Methyl- and 4-methyl-δ⁸-tetrahydrocannabinol: Correlation of spatial distinction with cannabinoid receptor binding

A high level of binding to the brain cannabinoid receptor was found for 2-methyl-Δ⁸-tetrahydrocannabinol (THC) while no binding was observed for 4-methyl-Δ⁸-THC. Four energy minima were found by molecular mechanics for ethyl side-chain models of Δ⁸-THC [syn- and antiperiplanar and (±)-orthogonal values for torsion angle C(4)-C(3)-C(α)-C(β)]. The active Δ⁸-THC and 2-methyl-Δ⁸-THC molecules share a common structural feature [a relatively low energy synperiplonar value C(4)-C(3)-C(α)-C(β) torsion angle conformation for the n-pentyl side chain] that is not exhibited by the inactive 4-methyl-Δ⁸-THC analogue. This spatial distinction may represent the basis for the difference in biological activity between the two isomers examined.