title: O-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties.
abstract: Cannabinoids have low water solubility, necessitating the use of a solubilizing agent. In this paper we investigated whether a novel water-soluble cannabinoid, 3-(5'-cyano-1', 1'-dimethylpentyl)-1-(4-N-morpholinobutyryloxy)-Delta(8)- tetrahydroca nnabinol hydrochloride (O-1057), would interact with cannabinoid receptors when water or saline were used as the only vehicle. O-1057 displaced [(3)H]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB(1) or CB(2) cannabinoid receptors, with pK(i) values of 8.36 and 7.95 respectively. It also displaced [(3)H]-CP55940 from specific binding sites on rat brain membranes (pK(i) = 7.86). O-1057 inhibited forskolin-stimulated cyclic AMP production by both CB(1)- and CB(2)-transfected CHO cells (pEC(50) = 9.16 and 9.72 respectively), its potency matching that of CP55940 and exceeding that of Delta(9)-tetrahydrocannabinol. In the mouse isolated vas deferens, O-1057 inhibited electrically-evoked contractions with pEC(50) and E(max) values of 9.73 and 76.84% respectively. It was antagonized by 100 nM SR141716A, the pK(B) of SR141716A against O-1057 (8.90) approximating to that against CP55940 (8.97). O-1057 also behaved as a CB(1) receptor agonist in vivo, reducing mouse spontaneous activity and rectal temperature when injected intravenously and inducing antinociception in the mouse tail flick test when given intravenously (ED(50) = 0.02 mg kg(-1)), intrathecally, intracerebroventricularly or by gavage. In all these assays, O-1057 was more potent than Delta(9)-tetrahydrocannabinol and, at 0.1 mg kg(-1) i.v., was antagonized by SR141716A (3 mg kg(-1) i.v.). These data demonstrate the ability of the water-soluble cannabinoid, O-1057, to act as a potent agonist at CB(1) and CB(2) receptors and warrant investigation of the clinical potential of O-1057 as an analgesic.
authors.affiliation: Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD. rgp@aberdeen.ac.uk
authors.forename: R G
authors.initials: RG
authors.lastname: Pertwee
authors.forename: T M
authors.initials: TM
authors.lastname: Gibson
authors.forename: L A
authors.initials: LA
authors.lastname: Stevenson
authors.forename: R A
authors.initials: RA
authors.lastname: Ross
authors.forename: W K
authors.initials: WK
authors.lastname: Banner
authors.forename: B
authors.initials: B
authors.lastname: Saha
authors.forename: R K
authors.initials: RK
authors.lastname: Razdan
authors.forename: B R
authors.initials: BR
authors.lastname: Martin
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology; D004347:Drug Interactions; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*; D012995:Solubility; D014316:Tritium; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D014867:Water / Q000737:chemistry
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D003511:Cyclohexanols; C409929:O 1057; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014867:Water; D014316:Tritium; D005576:Colforsin; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP