Evidence that (-)-7-hydroxy-4'-dimethylheptyl-cannabidiol activates a non-CB(1), non-CB(2), 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 (EC(50)=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 beta,gamma-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-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 microM; 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 microM) or capsazepine (10 microM). 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 CB(1) 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 CB(1), CB(2), TRPV1, opioid or alpha(2)-adrenergic receptor but do not exclude the possibility that it also activates CB(1) receptors.
Pertwee
Roger G
RG
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, Scotland, UK. rgp@abdn.ac.uk
Thomas
Adèle
A
Stevenson
Lesley A
LA
Maor
Yehoshua
Y
Mechoulam
Raphael
R
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D012430:Ruthenium Red / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology; D015016:Yohimbine / Q000494:pharmacology
C493219:6''-azidohex-2''-yne-cannabidiol; C542084:7-hydroxy-4'-dimethylheptylcannabidiol; D058669:Adrenergic alpha-2 Receptor Antagonists; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D012430:Ruthenium Red; D002185:Cannabidiol; D010656:Phenylephrine; D015016:Yohimbine; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D009270:Naloxone; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000255:Adenosine Triphosphate; C071423:capsazepine; D000077285:Rimonabant; D002211:Capsaicin