Stereoselective behavioral effects of Lu 19-005 in monkeys: relation to binding at cocaine recognition sites.
The effects of the monoamine uptake inhibitor Lu 19-005 ((+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-1-indanamine) and its (+) and (-) enantiomers, Lu 20-042 and Lu 20-043, were compared with those of cocaine and the selective dopamine uptake inhibitor GBR 12909 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine) in behavioral and radioligand binding experiments. Behavioral experiments were conducted in groups of squirrel monkeys trained under fixed-interval schedules of reinforcement in which responding was maintained either by presentation of food or by termination of a visual stimulus associated with mild electric shock. Radioligand binding studies were conducted using [3H]CFT and [3H]GBR 12935 to label elements of the dopamine uptake system in caudate-putamen membranes of cynomolgus monkeys. All drugs produced dose-related increases in response rate under the fixed-interval schedules. Lu 19-005, Lu 20-042, and Lu 20-043 had relatively slow onsets (approximately 2 h) and relatively long durations of action, with effects persisting for two or more days following administration. Stereoselectivity was evident in the behavioral effects of the enantiomers of Lu 19-005, with Lu 20-042 being approximately 14 times more potent than Lu 20-043. In radioligand binding experiments, Lu 19-005 and its enantiomers were potent inhibitors of specifically bound [3H]CFT and [3H]GBR 12935. As in behavioral experiments, Lu 20-042 was more potent than Lu 20-043. The degree of stereoselectivity, however, varied with the temperature of the assay medium.(ABSTRACT TRUNCATED AT 250 WORDS)
Rosenzweig-Lipson
S
S
Harvard Medical School, New England Regional Primate Research Center, Southborough, MA 01772-9102.
Bergman
J
J
Spealman
R D
RD
Madras
B K
BK
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D007189:Indans / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism*; D012055:Reinforcement Schedule; D012453:Saimiri; D013237:Stereoisomerism
D002352:Carrier Proteins; D007189:Indans; D008024:Ligands; D010879:Piperazines; D011955:Receptors, Drug; C061445:cocaine receptor; C043425:vanoxerine; C045117:Lu 19005; D003042:Cocaine; D004298:Dopamine