title: Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter.
abstract: BACKGROUND
  Treatment of stimulant-use disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like substitution therapies.
  
  
  METHODS
  This review focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinal-chemical perspective.
  
  
  RESULTS
  Possible mechanisms for atypicality at the molecular level can be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog is available, with a possible role of cholesterol, which is also present in the crystal of Drosophila DAT. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters.
  
  
  CONCLUSIONS
  Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse.
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: Maarten.Reith@nyumc.org.
authors.forename: Maarten E A
authors.initials: ME
authors.lastname: Reith
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.affiliation: Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Weimin C
authors.initials: WC
authors.lastname: Hong
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Kymry T
authors.initials: KT
authors.lastname: Jones
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Schmitt
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.affiliation: Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000494:pharmacology; D001590:Benztropine / Q000378:metabolism / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008024:Ligands; D000077408:Modafinil; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D001590:Benztropine; D003042:Cocaine; D000077408:Modafinil
keywords: Atypical effects; DA releasers; DAT inhibitors; Dopamine transporter; Molecular mechanisms; Stimulant abuse treatment compounds