3'-Chloro-3 alpha-(diphenylmethoxy)tropane but not 4'-chloro-3 alpha-(diphenylmethoxy)tropane produces a cocaine-like behavioral profile
| Autor: | Sari Izenwasser, Richard H. Kline, Amy Hauck Newman, Jonathan L. Katz, David B. Joseph, Wayne D. Bowen |
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| Rok vydání: | 1997 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Stereochemistry Dopamine Plasma Membrane Transport Proteins Dopamine Nerve Tissue Proteins Pharmacology Motor Activity Binding Competitive Mass Spectrometry Rats Sprague-Dawley chemistry.chemical_compound Discrimination Psychological Cocaine Dopamine Uptake Inhibitors Drug Discovery medicine Animals Neurotransmitter Dopamine transporter Benztropine Membrane Glycoproteins biology Dose-Response Relationship Drug Molecular Structure Membrane Transport Proteins Tropane Transporter Muscarinic acetylcholine receptor M1 Receptors Muscarinic Rats Neostriatum chemistry biology.protein Molecular Medicine Carrier Proteins medicine.drug Protein Binding Tropanes |
| Zdroj: | Journal of medicinal chemistry. 40(6) |
| ISSN: | 0022-2623 |
| Popis: | A series of 2'- and 3'-substituted and 3',3"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (Ki). Generally, meta-substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported para-substituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same meta-substituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K1 = 0.41-2.52 nM). Interestingly, 3'-chloro-3 alpha-(diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment. |
| Databáze: | OpenAIRE |
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