A Rational Search for the Separation of Psychoactivity and Analgesia in Cannabinoids
Chemistry & 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.
Reggio PH, McGaughey GB, Odear DF, Seltzman HH, Compton DR, Martin BR. 1991. A rational search for the separation of psychoactivity and analgesia in cannabinoids. Pharmacology Biochemistry and Behavior 40(3):479-86.