2-METHYL- AND 4-METHYL-DELTA(8)-TETRAHYDROCANNABINOL - CORRELATION OFSPATIAL DISTINCTION WITH CANNABINOID RECEPTOR-BINDING

A high level of binding to the brain cannabinoid receptor was found fo r 2-methyl-Delta(8)-tetrahydrocannabinol (THC) while no binding was ob served for 4-methyl-Delta(8)-THC. Four energy minima were found by mol ecular mechanics for ethyl side-chain models of Delta(8)-THC [syn- and antiperiplanar and (+/-)-orthogonal values for torsion angle C(4)-C(3 )-C(alpha)-C(beta)]. The active Delta(8)-THC and 2-methyl-Delta(8)-THC molecules share a common structural feature [a relatively low energy synperiplanar value C(4)-C(3)-C(alpha)-C(beta) torsion angle conformat ion for the n-pentyl side chain] that is not exhibited by the inactive 4-methyl-Delta(8)-THC analogue. This spatial distinction may represen t the basis for the difference in biological activity between the tn t wo isomers examined.