Chemical synthesis and biological occurrence of carboxylic acid metabolites of delta1(6)-tetrahydrocannabinol

Abstract

Potential metabolites of (-)-3,4-trans-tetrahydrocannabinol (THC) with a carboxylic acid function in the side chain were synthesized as their methyl esters in the delta1(6)-series. The chromatographic and mass-spectrometric properties of the five side-chain homologues were examined and utilized to facilitate the isolation and the identification of the corresponding monocarboxylic acid metabolites of delta1(6)-THC in the mouse, guinea pig, and rabbit formed after ip administration. The metabolites were identified by gas chromatography and mass fragmentography. In mouse liver delta1(6)-THC-7-oic acid and 3'',4'',5''-trisnor delta1(6)-THC-2''-oic acid were identified as metabolites. In guinea pig liver these acids occurred together with 4'',5''-bisnor-delta1(6)-THC-3''-oic acid and 5''-nor-delta1(6)-THC-4''-oic acid. Rabbit liver contained delta1(6)-THC-7-oic acid, 2'',3'',4'',5''-tetranor-delta1(6)-THC-1''-oic acid and 4'',5''-bisnor-delta1(6)-THC-3''-oic acid. Further, the structure of three dicarboxylic acid metabolites of delta1(6)-THC in rabbit kidney were determined by mass spectrometry and proton magnetic resonance spectroscopy.