title: Agonist-antagonist characterization of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol in two isolated tissue preparations.
abstract: This investigation was directed at characterizing some of the pharmacological properties of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol (O-823), a compound with high affinity for cannabinoid binding sites (Ki = 0.77 nM). In mouse vasa deferentia, O-823 behaved as a potent partial cannabinoid CB1 receptor agonist (EC50 = 0.015 nM). In the guinea-pig myenteric plexus preparation, it antagonized WIN 55.212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de ]-1, 4-benzoxazin-6-yl](1-naphthyl)methanone] and CP 55.940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl ) cyclohexan-1-ol] with Kd values of 0.65 and 0.27 nM, respectively. After in vivo delta 9-tetrahydrocannabinol pretreatment. the sensitivity of vasa deferentia to O-823-induced inhibition of electrically evoked contractions was reduced by 127-fold. 3.162 nM O-823 was inhibitory in unpretreated vasa deferentia but antagonized CP 55,940 in pretreated tissues (Kd = 0.26 nM). O-823 is probably an antagonist in the myenteric plexus preparation and delta 9-tetrahydro-cannabinol pretreated vasa deferentia but a partial agonist in unpretreated vasa deferentia because the first two of these preparations contain fewer receptors than the third.
authors.affiliation: Department of Biomedical Sciences, Marischal College, University of Aberdeen, Scotland, UK. rgp@aberdeen.ac.uk
authors.forename: R G
authors.initials: RG
authors.lastname: Pertwee
authors.forename: S R
authors.initials: SR
authors.lastname: Fernando
authors.forename: G
authors.initials: G
authors.lastname: Griffin
authors.forename: W
authors.initials: W
authors.lastname: Ryan
authors.forename: R K
authors.initials: RK
authors.lastname: Razdan
authors.forename: D R
authors.initials: DR
authors.lastname: Compton
authors.forename: B R
authors.initials: BR
authors.lastname: Martin
mesh_terms: D000700:Analgesics / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D048588:Benzoxazines; D001667:Binding, Competitive; D003511:Cyclohexanols / Q000378:metabolism; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007274:Injections, Intraperitoneal; D007421:Intestine, Small / Q000187:drug effects; D008297:Male; D051379:Mice; D009025:Morpholines / Q000037:antagonists & inhibitors; D009119:Muscle Contraction / Q000187:drug effects*; D009281:Naphthalenes / Q000037:antagonists & inhibitors; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors*; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; C104931:O 823; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol