title: Discriminative stimulus effects of BAY 38-7271, a novel cannabinoid receptor agonist.
abstract: BAY 38-7271 [(-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate] is a novel, highly potent and selective cannabinoid CB(1)/CB(2) receptor agonist with neuroprotective properties. It was the aim of the present study to further confirm its cannabinoid CB(1) receptor agonist properties in a highly sensitive in vivo assay. Male Wistar rats (n=24) were trained to discriminate BAY 38-7271 (0.05 mg/kg, i.p., t-30 min) from vehicle in a fixed-ratio:10, food-reinforced two-lever standard procedure. The animals acquired the discrimination after a median number of 52 training sessions. BAY 38-7271 generalized dose-dependently when tested after different routes of administration (ED(50): 0.018 mg/kg, i.p.; 0.001 microg/kg, i.v.; 0.18 mg/kg, p.o.). A time-dependency study indicated that the cue (0.05 mg/kg, i.p.) was detectable between 15 min and 4 h, with a maximum of generalization obtained at 30 min after administration. Pretreatment with the selective cannabinoid CB(1) receptor antagonist SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] completely antagonized the effects of BAY 38-7271 (ID(50): 1.1 mg/kg, i.p.). Dose-dependent and complete generalization was also obtained after i.p. administration of the reference cannabinoid CB(1) receptor agonists HU-210 [(-)-11-OH-Delta(8)-tetrahydrocannabinol-dimethylheptyl, ED(50): 0.003 mg/kg], CP 55,940 [(-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol, 0.007 mg/kg], WIN 55,212-2 [(R)-4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphtalenylcarbonyl)-6H-pyrrolo [3,2,1-ij] quinolin-6-one, 0.28 mg/kg] and (-)-Delta(9)-tetrahydrocannabinol (0.34 mg/kg). The present study confirms that BAY 38-7271 is a highly potent cannabinoid CB(1) receptor agonist in vivo.
authors.affiliation: CNS Research, Bayer Health Care, Aprather Weg 18a, D-42096 Wuppertal, Germany. jean.vry.jv1@bayer-ag.de
authors.forename: Jean
authors.initials: J
authors.lastname: De Vry
authors.forename: Klaus
authors.initials: K
authors.lastname: Rüdiger Jentzsch
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003216:Conditioning, Operant; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013451:Sulfonic Acids / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C459384:3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate; D007189:Indans; D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013451:Sulfonic Acids; D000077285:Rimonabant