Novel N-Substituted 3α-[Bis(4‘-fluorophenyl)methoxy]tropane Analogues:  Selective Ligands for the Dopamine Transporter

• Published in: Journal of medicinal chemistry 1997-12, Vol.40 (26), p.4329-4339
• Main Authors: Agoston, Gregory E, Wu, Jae H, Izenwasser, Sari, George, Clifford, Katz, Jonathan, Kline, Richard H, Newman, Amy Hauck
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain - metabolism; Carrier Proteins - metabolism; Catecholaminergic system; Cocaine - analogs & derivatives; Cocaine - metabolism; Cocaine - pharmacology; Crystallography, X-Ray; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors - chemical synthesis; Dopamine Uptake Inhibitors - chemistry; Dopamine Uptake Inhibitors - metabolism; Dopamine Uptake Inhibitors - pharmacology; Ligands; Male; Medical sciences; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Models, Molecular; Molecular Structure; Motor Activity - drug effects; Nerve Tissue Proteins; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Receptors, Muscarinic - metabolism; Structure-Activity Relationship; Tropanes - chemical synthesis; Tropanes - chemistry; Tropanes - metabolism; Tropanes - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970525a

A series of N-substituted 3α-[bis(4‘-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-3α-(diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it retained high affinity for muscarinic receptors. A series of N-substituted compounds were prepared from nor-3α-[bis(4‘-fluorophenyl)methoxy]tropane via acylation followed by hydride reduction of the amide or by direct alkylation. All compounds containing a basic tropane nitrogen displaced [3H]WIN 35,428 at the dopamine transporter (K i range = 8.5−634 nM) and blocked dopamine uptake (IC50 range = 10−371 nM) in rat caudate putamen, whereas ligands with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of binding affinities for the dopamine transporter versus muscarinic m1 receptors was achieved by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl, allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in this series at the dopamine transporter, N-(4‘‘-phenyl-n-butyl)-3α-[bis(4‘-fluorophenyl)methoxy]tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine abuse and other disorders affecting the dopamine transporter may be discovered.