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Reggio PH, McGaughey GB, Odear DF, Seltzman HH, Compton DR, Martin BR. 
“A rational search for the separation of psychoactivity and analgesia in cannabinoids”. 
Pharmacol Biochem Behav. 1991 Nov 14;40(3):479-86.
The compound 9-beta-hydroxy-hexahydrocannabinol [--9 beta-OH-HHC] was designed to fit a combined theoretical profile of an analgesic cannabinoid equatorial alcohol at C-9, phenol at C-1 and a C-3 side chain with reduced psychoactivity axial C-9 substituent which protrudes into the alpha face. --9 beta-OH-HHC was synthesized by the addition of methyl Grignard to 9-oxo-11-nor-HHC. Its alpha epimer was obtained by the regiospecific epoxide ring opening of 9 alpha, 10 alpha-epoxy-HHC acetate. --9 beta-OH-HHC and --9 alpha-OH-HHC were each evaluated in a battery of tests in mice and were found to be 10-25 times less potent than --trans-delta 9-tetrahydrocannabinol delta 9-THC in all tests including the tail flick test for antinociception analgesia. Molecular mechanics calculations [MMP285] revealed that, in the global minimum energy conformation of --9 beta-OH-HHC, the axial methyl at C-9 protrudes into the alpha face of the molecule, while the axial hydroxyl at C-9 in --9 alpha-OH-HHC protrudes into this same face. These calculations 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 alpha face. The minimal activity of both compounds is attributed to these higher energy forms.ABSTRACT TRUNCATED AT 250 WORDS
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