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 neurotics as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or beta,gamma-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 mu M; apparent K-B = 222.2 nM) but not by the CB, receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (I mu M) or capsazepine (10 mu M). 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 alpha(2)-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 alpha(2)-adrenergic receptor but do not exclude the possibility that it also activates CB1 receptors. (c) 2005 Elsevier Ltd. All rights reserved.