Evidence that (ÿ)-7-hydroxy-4#-dimethylheptyl-cannabidiol activates a non-CB 1 , non-CB 2 , non-TRPV1 target in the mouse vas deferens Roger G. Pertwee a, * , Ade`le Thomas a , Lesley A. Stevenson a , Yehoshua Maor b , Raphael Mechoulam b a School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK b Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University, Jerusalem 91120, Israel Received 9 September 2004; received in revised form 29 November 2004; accepted 20 January 2005 Abstract Previous experiments showed that R-(C)-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 (ÿ)-7-hydroxy-4#-dimethylheptyl-cannabidiol (7-OH-DMH- CBD) inhibits electrically-evoked contractions of the vas deferens (EC 50 Z 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 b,g-methylene- ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB 1 receptor antagonist than R-(C)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 mM; apparent K B Z 222.2 nM) but not by the CB 2 receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (1 mM) or capsazepine (10 mM). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(C)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of G i/o proteins from CB 1 receptors by a 2 - adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB 1 , CB 2 , TRPV1, opioid or a 2 -adrenergic receptor but do not exclude the possibility that it also activates CB 1 receptors. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: (ÿ)-7-hydroxy-4#-dimethylheptyl-cannabidiol (7-OH-DMH-CBD); Cannabidiol; R-(C)-WIN55212; Yohimbine; Mouse vas deferens; G i/o protein sequestration 1. Introduction Cannabis is the source of a set of at least 66 oxygen- containing aromatic hydrocarbon compounds that are known collectively as cannabinoids (reviewed in ElSohly, 2002). The most investigated of these has been D 9 -tetrahydrocannabinol which is generally regarded as being the main psychotropic constituent of cannabis (reviewed in Pertwee, 1988). Another plant cannabinoid that has been the subject of numerous pharmacological investigations is cannabidiol (Fig. 1) (reviewed in Pertwee, 2004a). This compound lacks psychoactivity. Even so, it is not pharmacologically inactive and can produce several effects that may come to be exploited therapeutically, for example anti-anxiety, anticonvul- sant and neuroprotective effects (reviewed in Pertwee, * Corresponding author. Tel.: C44 1224 555740; fax: C44 1224 555719. E-mail address: rgp@abdn.ac.uk (R.G. Pertwee). 0028-3908/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2005.01.010 Neuropharmacology 48 (2005) 1139e1146 www.elsevier.com/locate/neuropharm