Abstract
ABSTRACT
(−)‐
trans
‐Cannabidiol ((−)‐CBD) is a principal phytocannabinoid from
Cannabis sativa
. (−)‐CBD has complex pharmacology but is a relatively weak inhibitor of CB
1
and CB
2
receptor signaling. Cannabidiol has two chiral centres and thus four stereoisomers. (+)‐
trans
‐CBD ((+)‐CBD) has a higher affinity than (−)‐CBD at CB
1
and CB
2
, but its pharmacodynamic effects at these receptors are incompletely described. We examined the activity of (+)‐CBD at human CB
1
and CB
2
receptors using a fluorescence‐based assay of membrane potential in AtT20 cells stably expressing CB
1
or CB
2
receptors. (+)‐CBD produced a rapid, concentration‐dependent hyperpolarization in CB
2
‐expressing cells (
p
EC
50
6.63 ± 0.08) with a maximal effect 90% of the response to CP55940. The CB
2
response was blocked by pertussis toxin pretreatment and competitively inhibited by the CB
2
antagonist AM630 (Schild slope 1.1 ± 0.1). (+)‐CBD was a low‐efficacy, low‐potency CB
1
agonist and inhibited somatostatin‐receptor effects at high concentrations (10–30 μM). (+)‐CBD had no effect on the membrane potential of AtT20 wild‐type cells.
In silico
modeling of ligand interactions with CB
2
indicated that (+)‐CBD but not (−)‐CBD formed an H‐bond with Ser285, a residue crucial for agonist activation of CB
2
. Our data suggests (+)‐CBD acted as a CB
2
agonist via the orthosteric binding site on the receptor. Synthetic CBD, including (+)‐CBD, has previously been administered in clinical trials, presumably without consideration of its potential CB
2
agonist activity. Given the relative safety of (−)‐CBD in people, (+)‐CBD may be a useful drug to explore CB
2
‐sensitive disease states.