In vitro metabolism of (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol, a synthetic bicyclic cannabinoid analog

BF Thomas and BR Martin

Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0613.

The oxidative metabolism of CP-55,940 [(-)-cis-3-[2-hydroxy-4-(1,1- dimethylheptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol] was studied in mouse liver S-9 microsomal preparations. [3H]CP-55,940 was incubated in a microsomal supernatant enriched with the appropriate cofactors for cytochrome P-450 oxidative metabolism. HPLC separation of petroleum ether/diethyl ether (1:1) extracts facilitated the identification of metabolites by GC/MS after derivatization with BSTFA or [2H18]BSTFA. The mass spectral data indicated that five monohydroxylated metabolites had been formed that differed with respect to the position of hydroxylation on the 1',1'-dimethylheptyl side chain. Two additional compounds were detected whose mass spectral data suggested that these metabolites were hydroxylated at two positions on the side chain. Side chain hydroxylation is consistent with the metabolic profile of delta 9-tetrhydrocannabinol (delta 9-THC) and other cannabinoid compounds. It is possible that these side chain- hydroxylated metabolites retain activity, as is the case with similar metabolites formed from delta 9- and delta 8-THC, and thereby contribute to the pharmacological profile seen with this potent synthetic cannabimimetic agent.

Volume 18, Issue 6, pp. 1046-1054, 11/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics