Activation of CB2 Receptors by (−)-Cannabichromene but Not (+)-Cannabichromene

Abstract

Introduction:

Cannabichromene (CBC) is a minor constituent of cannabis that is a selective cannabinoid CB2 receptor agonist and activator of TRPA1. To date, it has not been shown whether (−)-CBC, (+)-CBC, or both can mediate these effects. In this study, we investigate the activity of the CBC enantiomers at CB1, CB2, and Transient receptor potential ankyrin 1 (TRPA1) receptors in vitro.

Materials and Methods:

CBC enantiomers were purified from synthetic CBC by chiral chromatography, and their optical activity was confirmed by spectroscopy. Human CB1 and CB2 receptor activity was measured using a fluorescent assay of membrane potential in stably transfected AtT20 cells. TRPA1 activation was measured using a fluorescent assay of intracellular calcium in stably transfected HEK293 cells.

Results:

The (−)-CBC activated CB2 with an EC₅₀ of 1.5 µM, to a maximum of 60% of (−)CP55940. (+)-CBC did not activate CB2 at concentrations up to 30 µM. Only 30 µM (−)-CBC produced detectable activation of CB1, (+)-CBC was inactive. Both (−)-CBC and (+)-CBC activated TRPA1; at 30 µM (−)-CBC produced an activation 50% of that of the reference agonist cinnamaldehyde (300 µM), 30 µM (+)-CBC activated TRPA1 to 38% of the cinnamaldehyde maximum.

Discussion:

It is unclear whether (−)-CBC is the sole or even the predominant enantiomer of CBC enzymatically synthesized in cannabis. This study shows that (−)-CBC is the active isomer at CB2 receptors, while both isomers activate TRPA1. The results suggest that medicinal preparations of CBC that target cannabinoid receptors would be most effective when (−)-CBC is the dominant isomer.