title: Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors.
abstract: The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (Ki= 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication.
authors.affiliation: 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.
authors.forename: Jianjing
authors.initials: J
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Slack
authors.affiliation: 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.
authors.forename: Oluyomi M
authors.initials: OM
authors.lastname: Bakare
authors.affiliation: 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 N. Wolfe Street, Baltimore, Maryland 21205, United States.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Burzynski
authors.affiliation: Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 N. Wolfe Street, Baltimore, Maryland 21205, United States.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.affiliation: Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine , 855 N. Wolfe Street, Baltimore, Maryland 21205, United States.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Psychobiology Section, Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , 251 Bayview Boulevard, Baltimore, Maryland 21224, United States.
authors.forename: Theresa
authors.initials: T
authors.lastname: Kopajtic
authors.affiliation: 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.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.affiliation: 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.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Ellenberger
authors.affiliation: 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.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yano
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.affiliation: 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.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Bi
authors.affiliation: 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.
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , DK-2200 Copenhagen, Denmark.
authors.forename: Claus J
authors.initials: CJ
authors.lastname: Loland
authors.affiliation: 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.
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D000077408:Modafinil; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D001559:Benzhydryl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D000077408:Modafinil