Molecular Pharmacology, Vol 12, 345-352, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Some Structural Requirements for Inhibition of High-Affinity Synaptosomal Serotonin Uptake by Cannabinoids

¹ Department of Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

The effect of ⁹-tetrahydrocannabinol (⁹-THC) and 18 of its metabolites and analogues on the high-affinity uptake of [³H]serotonin into a synaptosome-enriched homogenate of rat forebrain has been determined in vitro. Each of the cannabinoids which inhibited [³H]serotonin accumulation did so in a dose-responsive manner. Although some of these compounds do not possess typical ⁹-THC or marijuana-like effects in laboratory animals or humans, each of the cannabinoids tested, with one exception, inhibited the uptake of serotonin at the concentrations used. A positional activity requirement for the phenolic hydroxyl group was demonstrated by the increased IC₅₀ values for the abnormal analogues of ⁸-THC and cannabidiol relative to their parent compounds. ⁸-THC and cannabinol were slightly more active than ⁹-THC, implying that the orientation of protons at the C-8 position may be important for activity. Pseudoequatorial hydroxylation of C-8 resulted in diminished activity, while pseudoaxial hydroxylation of C-8 resulted in little change. In addition, equatorial hydroxylation of C-9 diminished activity relative to axial hydroxylation of C-9. It was also found that hydroxylation of C-9 increased the IC-₅₀ almost 3-fold relative to the C-9 methylated compound. Finally, it was determined that nonpolar substitution at C-11 diminished the activity only slightly compared to the reduction obtained by hydroxylation of C-11.