3'-Hydroxy- and (±)-3',11-dihydroxy-Δ9-tetrahydrocannabinol: Biologically active metabolites of Δ9-tetrahydrocannabinol

Article abstract of DOI:10.1021/jm00354a011

Synthesis of 3'-Hydroxy- (7) and (±)-3',11-dihydroxy-Δ⁹-tetrahydrocannabinol (11), metabolites of Δ⁹-THC, is described. Condensation of the monoterpene (±)-cis-p-menth-2-ene-1,8-diol (1) and (±)-3'-acetoxyolivetol (2) in the presence of fused ZnCl₂ in CH₂Cl₂ gave a mixture from which the Δ⁹-THC derivative 3, containing small amounts of the Δ⁸ isomer 4, was isolated after column chromatography. This mixture was separated as their diacetates 5 and 6 by high-pressure liquid chromatography. Alkaline hydrolysis (5% KOH in MeOH) of 5 furnished the metabolite 7. Condensation of (±)-8 with 2 in the presence of p-toluenesulfonic acid gave 9a, which was acetylated to 9b. Treatment with HgO/BF₃.Et₂O in wet THF gave the aldehyde 10. Reduction with LiAlH₄ furnished the metabolite 11. These metabolites were compared with Δ⁹-THC for their ability to depress spontaneous activity and rectal temperature in mice and for their effects on overt behavior in dogs. 3'-Hydroxy-Δ⁹-THC was also compared to Δ⁹-THC in the mouse sympatomatology test and cardiovascular system in dogs. The metabolites produced pharmacological effects similar to those of Δ⁹-THC in all tests. 3'-Hydroxy-Δ⁹-THC was 2-3 times more effective than Δ⁹-THC in the behavioral tests, whereas (±)-3',11-dihydroxy-Δ⁹-THC was approximately 3 times less active than Δ⁹-THC.