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

K. M. Johnson, W. L. Dewey, L. S. Harris

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)345-352
Number of pages8
JournalMolecular Pharmacology
Volume12
Issue number3
StatePublished - 1976
Externally publishedYes

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Cannabinoids
Hydroxylation
Dronabinol
Serotonin
Inhibitory Concentration 50
Cannabinol
Cannabidiol
Synaptosomes
Laboratory Animals
Cannabis
Prosencephalon
Hydroxyl Radical
Protons

ASJC Scopus subject areas

  • Pharmacology

Cite this

Some structural requirements for inhibition of high affinity synaptosomal serotonin uptake by cannabinoids. / Johnson, K. M.; Dewey, W. L.; Harris, L. S.

In: Molecular Pharmacology, Vol. 12, No. 3, 1976, p. 345-352.

Research output: Contribution to journalArticle

Johnson, K. M. ; Dewey, W. L. ; Harris, L. S. / Some structural requirements for inhibition of high affinity synaptosomal serotonin uptake by cannabinoids. In: Molecular Pharmacology. 1976 ; Vol. 12, No. 3. pp. 345-352.
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