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 S. Slusher; Lei Shi; Claus J. Loland; Amy Hauck Newman

doi:10.1021/acs.jmedchem.7b01454

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 S. Slusher, Lei Shi, Claus J. Loland, Amy Hauck Newman^*

^*Corresponding author af dette arbejde

Neuropharm and Genetics

7 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	60
Udgave nummer	24
Sider (fra-til)	10172-10187
Antal sider	16
ISSN	0022-2623
DOI	https://doi.org/10.1021/acs.jmedchem.7b01454
Status	Udgivet - dec. 2017

Adgang til dokumentet

10.1021/acs.jmedchem.7b01454

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Citationsformater

Zou, M. F., Cao, J., Abramyan, A. M., Kopajtic, T., Zanettini, C., Guthrie, D. A., Rais, R., Slusher, B. S., Shi, L., Loland, C. J., & Newman, A. H. (2017). 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. Journal of Medicinal Chemistry, 60(24), 10172-10187. https://doi.org/10.1021/acs.jmedchem.7b01454

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. et al.

I: Journal of Medicinal Chemistry, Bind 60, Nr. 24, 12.2017, s. 10172-10187.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Zou, MF, Cao, J, Abramyan, AM, Kopajtic, T, Zanettini, C, Guthrie, DA, Rais, R, Slusher, BS, Shi, L, Loland, CJ & Newman, AH 2017, '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', Journal of Medicinal Chemistry, bind 60, nr. 24, s. 10172-10187. https://doi.org/10.1021/acs.jmedchem.7b01454

Zou MF, Cao J, Abramyan AM, Kopajtic T, Zanettini C, Guthrie DA et al. 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. Journal of Medicinal Chemistry. 2017 dec.;60(24):10172-10187. doi: 10.1021/acs.jmedchem.7b01454

Zou, Mu Fa ; Cao, Jianjing ; Abramyan, Ara M. et al. / 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. I: Journal of Medicinal Chemistry. 2017 ; Bind 60, Nr. 24. s. 10172-10187.

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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.",

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