Evidence that (-)-7-hydroxy-4′-dimethylheptyl-cannabidiol activates a non-CB₁, non-CB₂, non-TRPV1 target in the mouse vas deferens

Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4′-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC₅₀ = 13.3 nM). This it appeared to do by acting on prejunctional neurones as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or β,γ-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB₁ receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 μM; apparent K_B = 222.2 nM) but not by the CB ₂ receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (1 μM) or capsazepine (10 μM). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of G_i/o proteins from CB₁ receptors by α₂-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB₁, CB₂, TRPV1, opioid or α₂-adrenergic receptor but do not exclude the possibility that it also activates CB₁ receptors.