6″-Azidohex-2″-yne-cannabidiol: A potential neutral, competitive cannabinoid CB₁ receptor antagonist

Previous experiments with the mouse vas deferens have shown that cannabidiol produces surmountable antagonism of cannabinoid CB₁ receptor agonists at concentrations well below those at which it binds to cannabinoid CB₁ receptors and antagonizes α₁- adrenoceptor agonists insurmountably. It also enhances electrically evoked contractions of this tissue. We have now found that subtle changes in the structure of cannabidiol markedly influence its ability to produce each of these effects, suggesting the presence of specific pharmacological targets for this non-psychoactive cannabinoid. Our experiments were performed with cannabidiol, 6-azidohex-2-yne-cannabidiol, abnormal-cannabidiol and 2′-monomethoxy- and 2′,6′-dimethoxy-cannabidiol. Of these, 6-azidohex-2-yne-cannabidiol was as potent as cannabidiol in producing surmountable antagonism of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) in vasa deferentia. However, it produced this antagonism with a potency that matched its cannabinoid CB₁ receptor affinity, suggesting that, unlike cannabidiol, it is a competitive cannabinoid CB₁ receptor antagonist. Moreover, since it did not enhance the amplitude of electrically evoked contractions, it may be a neutral cannabinoid CB₁ receptor antagonist.