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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.
J Med Chem. 2017 12 28; 60(24):10172-10187.JM

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.

Authors+Show Affiliations

Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.Psychobiology Section, Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States.Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 North Wolfe Street, Baltimore, Maryland 21205, United States.Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 North Wolfe Street, Baltimore, Maryland 21205, United States.Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.Molecular Faculty of Health and Medical Sciences, University of Copenhagen , DK-2200 Copenhagen, Denmark.Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29227643

Citation

Zou, Mu-Fa, 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, vol. 60, no. 24, 2017, pp. 10172-10187.
Zou MF, Cao J, Abramyan AM, 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. J Med Chem. 2017;60(24):10172-10187.
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
Zou MF, 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. J Med Chem. 2017 12 28;60(24):10172-10187. PubMed PMID: 29227643.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2017/12/11/ PY - 2017/12/12/pubmed PY - 2019/4/2/medline PY - 2017/12/12/entrez SP - 10172 EP - 10187 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 60 IS - 24 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/29227643/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 L2 - https://dx.doi.org/10.1021/acs.jmedchem.7b01454 DB - PRIME DP - Unbound Medicine ER -