Structure-Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders

Mu Fa Zou, Jianjing Cao, Ara M. Abramyan, Theresa Kopajtic, Claudio Zanettini, Daryl A. Guthrie, Rana Rais, Barbara Slusher, Lei Shi, Claus J. Loland, Amy Hauck Newman

Research output: Contribution to journalArticle

Abstract

The development of medications to treat cocaine use disorders has thus far defied success, leaving this patient population without pharmacotherapeutic options. As the dopamine transporter (DAT) plays a prominent role in the reinforcing effects of cocaine that can lead to addiction, atypical DAT inhibitors have been developed that prevent cocaine from binding to DAT, but they themselves are not cocaine-like. Herein, a series of novel DAT inhibitors were synthesized, and based on its pharmacological profile, the lead compound 10a was evaluated in phase I metabolic stability studies in mouse liver microsomes and compared to cocaine in locomotor activity and drug discrimination paradigms in mice. A molecular dynamic simulation study supported the hypothesis that atypical DAT inhibitors have similar binding poses at DAT in a conformation that differs from that of cocaine. Such differences may ultimately contribute to their unique behavioral profiles and potential for development as cocaine use disorder therapeutics.

Original languageEnglish (US)
Pages (from-to)10172-10187
Number of pages16
JournalJournal of Medicinal Chemistry
Volume60
Issue number24
DOIs
StatePublished - Dec 28 2017

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Tropanes
Dopamine Plasma Membrane Transport Proteins
Structure-Activity Relationship
Cocaine
Therapeutics
Liver Microsomes
Therapeutic Uses
Molecular Dynamics Simulation
Locomotion
Pharmacology

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structure-Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders. / Zou, Mu Fa; Cao, Jianjing; Abramyan, Ara M.; Kopajtic, Theresa; Zanettini, Claudio; Guthrie, Daryl A.; Rais, Rana; Slusher, Barbara; Shi, Lei; Loland, Claus J.; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 60, No. 24, 28.12.2017, p. 10172-10187.

Research output: Contribution to journalArticle

Zou, Mu Fa ; Cao, Jianjing ; Abramyan, Ara M. ; Kopajtic, Theresa ; Zanettini, Claudio ; Guthrie, Daryl A. ; Rais, Rana ; Slusher, Barbara ; Shi, Lei ; Loland, Claus J. ; Newman, Amy Hauck. / Structure-Activity Relationship Studies on a Series of 3α-[Bis(4-fluorophenyl)methoxy]tropanes and 3α-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 24. pp. 10172-10187.
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