Investigation of the Role of the Phenolic Hydroxyl in Cannabinoid Activity
Chemistry & Biochemistry
Structure-activity relationship studies have suggested that the phenolic hydroxyl group is essential for the pharmacol. activity of the cannabinoids. However, it remains to be established whether it is the hydrogen of the phenolic hydroxyl that is important (possibly because this hydrogen can participate in a hydrogen bonding interaction) or whether it is the oxygen of the phenolic hydroxyl that is important (possibly because one of the lone pairs of electrons on this oxygen can serve as a hydrogen bond acceptor). Two new etherified cannabinoids were prepd. in which the phenolic hydroxyl oxygen is incorporated into a fourth ring. These new compds. were designed to test the importance both of the phenolic hydroxyl oxygen and of the orientation of its lone pairs of electrons for cannabinoid pharmacol. activity. O,2-Propano-Δ8-tetrahydrocannabinol (0,2-Propano-Δ8-THC) was designed to mimic Δ9-THC in its phenol conformation I (C2-C1-O-H-7°). O,10-Methano-Δ9-tetrahydrocannabinol (0,10-Methano-Δ9-THC) was designed to mimic Δ9-THC in its phenol conformation II (C2-C1-O-H = 167°). Mol. mechanics calcns. revealed that 1) there are two accessible min. energy conformers for O,2-propano-Δ8-THC, which differ principally in the conformation of the new fourth ring, and 2) there are three accessible min. energy conformers for O,10-methano-Δ9-THC, the first two of which differ mainly in the conformation of the new fourth ring, whereas the third possesses an alternate pyran ring conformation. Wave function and mol. electrostatic potential (MEP) maps were calcd. for each accessible conformer of O,2-propano-Δ8-THC and of O,10-methano-Δ9-THC. The resultant MEP maps compared well with the corresponding MEP maps generated for Δ9-THC in each of its two min. energy conformations (two phenolic hydroxyl positions). These results imply that 1) O,2-propano-Δ8-THC should be capable of being recognized at a site that would recognize Δ9-THC in its phenol conformation I and 2) O,10-methano-Δ9-THC should be capable of being recognized at a site that would recognize Δ9-THC in its phenol conformation II. Pharmacol. evaluation of the analogs revealed that O,10-methano-Δ9-THC was inactive in all mouse tests, as well as the rat drug discrimination model. O,2-Propano-Δ8-THC was similar to Δ8-THC in that it depressed rectal temp. and produced antinociception and ring immobility in mice. However, it differed from Δ8-THC in that it only weakly depressed locomotor activity and failed to substitute for Δ9-THC in the drug discrimination paradigm. A similar sepn. of cannabinoid pharmacol. effects has not been possible heretofore. These results suggest that the orientation of the lone pairs of electrons on the phenolic hydroxyl oxygen plays an important role in the mediation of some, but not all, behavioral effects of the cannabinoids.
Reggio RH, Seltzman HH, Compton DR, Prescott Jr WR, Martin, BR. 1990. Investigation of the role of the phenolic hydroxyl in cannabinoid activity. Molecular Pharmacology 38(6):854-62.