Novel N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues: Selective ligands for the dopamine transporter

Gregory E. Agoston, Jae H. Wu, Sari Izenwasser, Clifford George, Jonathan Katz, Richard H. Kline, Amy Hauck Newman

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4329-4339
Number of pages11
JournalJournal of Medicinal Chemistry
Volume40
Issue number26
DOIs
StatePublished - 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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