title: 3'-Hydroxy- and (+/-)-3',11-dihydroxy-delta 9-tetrahydrocannabinol: biologically active metabolites of delta 9-tetrahydrocannabinol.
abstract: Synthesis of 3'-hydroxy- (7) and (+/-)-3',11-dihydroxy-delta 9-tetrahydrocannabinol (11), metabolites of delta 9-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 delta 9-THC derivative 3, containing small amounts of the delta 8-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 X Et2O in wet THF gave the aldehyde 10. Reduction with LiAlH4 furnished the metabolite 11. These metabolites were compared with delta 9-THC for their ability to depress spontaneous activity and rectal temperature in mice and for their effects on overt behavior in dogs. 3'-Hydroxy-delta 9-THC was also compared to delta 9-THC in the mouse sympatomatology test and cardiovascular system in dogs. The metabolites produced pharmacological effects similar to those of delta 9-THC in all tests. 3'-Hydroxy-delta 9-THC was 2-3 times more effective than delta 9-THC in the behavioral tests, whereas (+/-)-3',11-dihydroxy-delta 9-THC was approximately 3 times less active than delta 9-THC.
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects
chemical_list: C036735:3'-hydroxy-delta(9)-tetrahydrocannabinol; C036736:3',11-dihydroxy-delta(9)-tetrahydrocannabinol; D013759:Dronabinol