PT  - JOURNAL ARTICLE
AU  - JOHNSON, KENNETH M.
AU  - DEWEY, WILLIAM L.
AU  - HARRIS, LOUIS S.
TI  - Some Structural Requirements for Inhibition of High-Affinity Synaptosomal Serotonin Uptake by Cannabinoids
DP  - 1976 May 01
TA  - Molecular Pharmacology
PG  - 345--352
VI  - 12
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/12/3/345.short
4100  - http://molpharm.aspetjournals.org/content/12/3/345.full
SO  - Mol Pharmacol1976 May 01; 12
AB  - 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 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.