Some structural requirements for inhibition of high affinity synaptosomal serotonin uptake by cannabinoids

The effect of Δ⁹ tetrahydrocannabinol (Δ⁹ 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 Δ⁹ 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 Δ⁸ THC and cannabidiol relative to their parent compounds. Δ⁸ THC and cannabinol were slightly more active than Δ⁹ 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 IC₅₀ 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.