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 for this work

Neuropharm and Genetics

7 Citations (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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	24
Pages (from-to)	10172-10187
Number of pages	16
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.7b01454
Publication status	Published - Dec 2017

Access to Document

10.1021/acs.jmedchem.7b01454

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this

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.

In: Journal of Medicinal Chemistry, Vol. 60, No. 24, 12.2017, p. 10172-10187.

Research output: Contribution to journal › Journal article › Research › 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, vol. 60, no. 24, pp. 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. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 24. pp. 10172-10187.

@article{d0496f0e738341ffa2d7ca1446e13bc7,

title = "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",

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.",

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

year = "2017",

month = dec,

doi = "10.1021/acs.jmedchem.7b01454",

language = "English",

volume = "60",

pages = "10172--10187",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "24",

}

TY - JOUR

T1 - 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

AU - Zou, Mu Fa

AU - Cao, Jianjing

AU - Abramyan, Ara M.

AU - Kopajtic, Theresa

AU - Zanettini, Claudio

AU - Guthrie, Daryl A.

AU - Rais, Rana

AU - Slusher, Barbara S.

AU - Shi, Lei

AU - Loland, Claus J.

AU - Newman, Amy Hauck

PY - 2017/12

Y1 - 2017/12

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.7b01454

DO - 10.1021/acs.jmedchem.7b01454

M3 - Journal article

C2 - 29227643

AN - SCOPUS:85040014872

SN - 0022-2623

VL - 60

SP - 10172

EP - 10187

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -