A Rational Search for the Separation of Psychoactivity and Analgesia in Cannabinoids
Chemistry and Biochemistry
The compd. 9-
beta-hydroxy-hexahydrocannabinol [(-)-9β-OH-HHC] was designed to fit a combined theor. profile of an analgesic cannabinoid (equatorial alc. at C-9, phenol at C-1 and a C-3 side chain) with reduced psychoactivity (axial C-9 substituent which protrudes into the α face). (-)-9β-OH-HHC was synthesized by the addn. of Me Grignard to 9-oxo-11-nor-HHC. Its α epimer was obtained by the regiospecific epoxide ring opening of 9α, 10α-epoxy-HHC acetate. (-)-9β-OH-HHC and (-)-9α-OH-HHC were each evaluated in a battery of tests in mice and were found to be 10-25 times less potent than (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC) in all tests including the tail flick test for antinociception (analgesia). Mol. mechanics calcns. [MMP2(85)] revealed that, in the global min. energy conformation of (-)-9β-OH-HHC, the axial Me at C-9 protrudes into the α face of the mol., while the axial hydroxyl at C-9 in (-)-9α-OH-HHC protrudes into this same face. These calcns. also identified a higher energy carbocyclic ring (twist) conformer of each in which there is no protrusion of a C-9 substituent of the carbocyclic ring into the α face. The minimal activity of both compds. is attributed to these higher energy forms. It is concluded that protrusion of a C-9 substituent into the α-face of the mol. is assocd. with reduced cannabinoid analgesia, as well as with reduced cannabinoid psychopharmacol. activity.