Differential Enantiomer-Specific Signaling of Cannabidiol at CB1 Receptors

Mol Pharmacol. 2022 Dec;102(6):259-268. doi: 10.1124/molpharm.121.000305. Epub 2022 Sep 24.

Abstract

The two main constituents of <i>cannabis</i> are Δ<sup>9</sup>-tetrahydrocannabinol (THC) and cannabidiol (CBD). While Δ<sup>9</sup>-THC pharmacology has been studied extensively, CBD-long considered inactive-is now the subject of vigorous research related to epilepsy, pain, and inflammation and is popularly embraced as a virtual cure-all. However, our understanding of CBD pharmacology remains limited, although CBD inhibits cannabinoid CB<sub>1</sub> receptor signaling, likely as a negative allosteric modulator. <i>Cannabis</i> synthesizes (-)-CBD, but CBD can also exist as an enantiomer, (+)-CBD. We enantioselectively synthesized both CBD enantiomers using established conditions and describe here a new, practical, and reliable, NMR-based method for confirming the enantiomeric purity of two CBD enantiomers. We also investigated the pharmacology of (+)-CBD in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and in CHO-K1 cells. We report the inhibition constant for displacing CP55,940 at CB<sub>1</sub> by (+)-CBD, is 5-fold lower than (-)-CBD. We find that (+)-CBD is ∼10 times more potent at inhibiting depolarization-induced suppression of excitation (DSE), a form of endogenous cannabinoid-mediated retrograde synaptic plasticity. (+)-CBD also inhibits CB<sub>1</sub> suppression of cAMP accumulation but with less potency, indicating that the signaling profiles of the enantiomers differ in a pathway-specific manner. In addition, we report that (+)-CBD stereoselectively and potently activates the sphingosine-1 phosphate (S1P) receptors, S1P<sub>1</sub> and S1P<sub>3</sub> These results provide an attractive method for synthesizing and distinguishing enantiomers of CBD and related phytocannabinoids and provide further evidence that these enantiomers have their own unique and interesting signaling properties. SIGNIFICANCE STATEMENT: Cannabidiol (CBD) is the subject of considerable scientific and popular interest, but we know little of the enantiomers of CBD. We find that the enantiomer (+)-CBD is substantially more potent inhibitor of cannabinoid CB<sub>1</sub> receptors and that it activates sphingosine-1-phosphate receptors in an enantiomer-specific manner; we have additionally developed an improved method for the synthesis of enantiomers of CBD and related compounds.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cannabidiol* / pharmacology
  • Cannabinoid Receptor Agonists / pharmacology
  • Dronabinol / pharmacology
  • Endocannabinoids
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Signal Transduction

Substances

  • Cannabidiol
  • Dronabinol
  • Cannabinoid Receptor Agonists
  • Endocannabinoids
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2