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

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

Research output: Contribution to journalArticle

99 Citations (Scopus)

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
Pages (from-to)4329-4339
Number of pages11
JournalJournal of Medicinal Chemistry
Volume40
Issue number26
DOIs
StatePublished - Dec 1 1997
Externally publishedYes

Fingerprint

Tropanes
Dopamine Plasma Membrane Transport Proteins
Ligands
Benztropine
Cocaine
Rats
Nitrogen
Dopamine Uptake Inhibitors
Muscarinic M1 Receptors
Norepinephrine Plasma Membrane Transport Proteins
Acylation
Cocaine-Related Disorders
Serotonin Plasma Membrane Transport Proteins
Putamen
Alkylation
Muscarinic Receptors
Amides
Hydrides
Inhibitory Concentration 50
Dopamine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues : Selective ligands for the dopamine transporter. / Agoston, Gregory E.; Wu, Jae H.; Izenwasser, Sari E; George, Clifford; Katz, Jonathan; Kline, Richard H.; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 40, No. 26, 01.12.1997, p. 4329-4339.

Research output: Contribution to journalArticle

Agoston, Gregory E. ; Wu, Jae H. ; Izenwasser, Sari E ; George, Clifford ; Katz, Jonathan ; Kline, Richard H. ; Newman, Amy Hauck. / Novel N-substituted 3α-[bis(4'-fluorophenyl)methoxy]tropane analogues : Selective ligands for the dopamine transporter. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 26. pp. 4329-4339.
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