Discriminative stimulus effects of the structurally novel cannabinoid CB1/CB2 receptor partial agonist BAY 59-3074 in the rat.
BAY 59-3074 [3-[2-cyano-3-(trifluoromethyl)phenoxy]phenyl-4,4,4-trifluoro-1-butane-sulfonate] is a structurally novel cannabinoid CB1/CB2 receptor partial agonist with analgesic properties. The present study was performed to confirm its receptor binding profile in a highly sensitive in vivo assay. Rats (n=10) learned to discriminate BAY 59-3074 (0.5 mg/kg, p.o., t-1 h) from vehicle in a fixed-ratio: 10, food-reinforced two-lever procedure after a median number of 28 training sessions. BAY 59-3074 generalized dose-dependently (ED(50): 0.081 mg/kg, p.o.) and the cue was detectable between 0.25 and 4 h after administration. The selective cannabinoid CB1 receptor antagonist SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] blocked the discriminative effects of BAY 59-3074 (ID50: 1.79 mg/kg, i.p.). Complete generalization was also obtained after i.p. administration of BAY 59-3074 (ED50 value: 0.41 mg/kg), and the reference cannabinoids BAY 38-7271 [(-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-butanesulfonate, 0.011 mg/kg], CP 55,940 [(-)-cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol, 0.013 mg/kg], HU-210 [(-)-11-OH-Delta8-tetrahydrocannabinol dimethylheptyl, 0.022 mg/kg], WIN 55,212-2 [(R)-4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo [3,2,1-ij] quinolin-6-one, 0.41 mg/kg] and (-)-Delta9-tetrahydrocannabinol (0.41 mg/kg). Non-cannabinoids with analgesic properties, such as morphine, amitriptyline, carbamazepine, gabapentin and baclofen, did not generalize to the cue. It is concluded that the discriminative stimulus effects of BAY 59-3074 are specifically mediated by cannabinoid CB1 receptor activation.
De Vry
Jean
J
CNS Research, Bayer HealthCare, Aprather Weg 18a, 42096 Wuppertal, Germany. jean.devry@grunenthal.de
Jentzsch
Klaus Rüdiger
KR
D000476:Alkanesulfonates / Q000737:chemistry / Q000494:pharmacology*; D000588:Amines / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines; D002220:Carbamazepine / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077206:Gabapentin; D007189:Indans / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009020:Morphine / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
C498148:3-(2-cyano-3-(trifluoromethyl)phenoxy)phenyl-4,4,4-trifluoro-1-butanesulfonate; C459384:3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate; D000476:Alkanesulfonates; D000588:Amines; D048588:Benzoxazines; D003509:Cyclohexanecarboxylic Acids; D003511:Cyclohexanols; D007189:Indans; D009025:Morpholines; D009281:Naphthalenes; D009570:Nitriles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013451:Sulfonic Acids; D000639:Amitriptyline; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077206:Gabapentin; D009020:Morphine; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D001418:Baclofen; C062018:HU 211