The pharmacological actions of cannabidiol and its derivatives
- This study was directed at exploring the method(s) by which cannabidiol is capable of antagonizing the cannabinoid CB1/CB2 receptor agonist (R-(+)-WIN55212 in the mouse isolated vas deferens tissue preparation. - The mechanism appeared not to involve competition at the cannabinoid CB1 receptor, since the CB1 Ki binding potency (4.9 mM) was significantly less than the apparent KB antagonizing potency (71.4 nM) for the antagonism of R-(+)-WIN55212 in the isolated mouse vas deferens. Additionally, the ability of cannabidiol to antagonize R-(+)-WIN55212 in the mouse isolated van deferens was not reproduced in the guinea-pig myenteric plexus-longitudinal muscle (MPLM) preparation; a tissue that like the mouse vas deferens expresses cannabinoid CB1 receptors. - Evidence was generated that suggested the antagonism of R-(+)-WIN55212 by cannabidiol was not through a non-specific mechanism, since the pharmacological properties investigated displayed structural-dependence. Furthermore cannabidiol exhibited stereoselectivity as an antagonist of R-(+)-WIN55212. - The cannabidiol analogue, 6”-azidohex-2”-yne-cannabidiol (O-2654) displayed a higher affinity than cannabidiol for cannabinoid CB1 receptors (Ki = 114.4 nM) and cannabinoid CB2 receptors (Ki = 54.4 nM). Unlike, cannabidiol, O-2654, appeared to antagonize R-(+)-WIN55212 in the mouse isolated vas deferens by behaving as a neutral cannabinoid CB1 receptor antagonist, since the apparent KB value (85.7 nM) for this antagonism was not significantly different from the determined CB1 Ki value. - Another analogue of cannabidiol, 7-OH-DMH-CBD, was observed to potently inhibit electrically evoked contractions of the mouse isolated vas deferens (EC50 = 13.3 nM) at a putative site that was demonstrated to be a non-CB1, non-CB2, non-TRPV1, non-a2-adrenergic and non-opioid molecular target that is sensitive to antagonism by cannabidiol. - Together these data have identified a novel target for cannabinoids and a cannabidiol analogue that behaves as a neutral cannabinoid CB1 receptor antagonist.