Novel 4′-substituted and 4′,4″-disubstituted 3α-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors

Amy Hauck Newman, Richard H. Kline, Andrew C. Allen, Sari E Izenwasser, Clifford George, Jonathan L. Katz

Research output: Contribution to journalArticle

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Abstract

A series of 4′-substituted and 4′,4″-disubstituted 3α-(diphenylmethoxy)tropane analogs were prepared as novel probes for the dopamine transporter. These compounds were evaluated in radiolabeled binding assays for the dopamine, norepinephrine, and serotonin transporters. All of these compounds monophasically displaced [3H]WIN 35,428 binding in rat caudate putamen with Ki values ranging from 11.8 to 2000 nM. The most potent compound in this series was 4′,4″-difluoro 3α-(diphenylmethoxy)tropane 7c with a Ki = 11.8 nM. All of the compounds inhibited dopamine uptake in rat caudate putamen (IC50 = 24-4456 nM) which correlated significantly (r = 0.907; p > 0.0001) with binding affinities at the dopamine transporter. None of the compounds demonstrated high-affinity binding at the norepinephrine (Ki > 4800 nM) or serotonin (Ki > 690 nM) transporters. Therefore, the most potent dopamine uptake inhibitors in this series were highly selective for the dopamine transporter. Preliminary behavioral studies of several of these analogs (7a-e) suggested that the compounds did not display a cocaine-like behavioral profile, despite their ability to inhibit dopamine uptake. The present data coupled with the observed differences from cocaine in structure-activity relationships suggested that the 3α-(diphenylmethoxy)tropane analogs may be interacting at a different active site than cocaine on the dopamine transporter and that an additional binding domain might be exploited for the identification of potential therapeutics for the treatment of cocaine abuse.

Original languageEnglish
Pages (from-to)3933-3940
Number of pages8
JournalJournal of Medicinal Chemistry
Volume38
Issue number20
StatePublished - Dec 1 1995
Externally publishedYes

Fingerprint

Dopamine Uptake Inhibitors
Tropanes
Dopamine Plasma Membrane Transport Proteins
Cocaine
Putamen
Rats
Dopamine
Norepinephrine Plasma Membrane Transport Proteins
Cocaine-Related Disorders
Serotonin Plasma Membrane Transport Proteins
Aptitude
Structure-Activity Relationship
Inhibitory Concentration 50
Assays
Catalytic Domain
Serotonin
Norepinephrine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel 4′-substituted and 4′,4″-disubstituted 3α-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors. / Newman, Amy Hauck; Kline, Richard H.; Allen, Andrew C.; Izenwasser, Sari E; George, Clifford; Katz, Jonathan L.

In: Journal of Medicinal Chemistry, Vol. 38, No. 20, 01.12.1995, p. 3933-3940.

Research output: Contribution to journalArticle

Newman, Amy Hauck ; Kline, Richard H. ; Allen, Andrew C. ; Izenwasser, Sari E ; George, Clifford ; Katz, Jonathan L. / Novel 4′-substituted and 4′,4″-disubstituted 3α-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 20. pp. 3933-3940.
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