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Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile.
Okorom, Amarachi V; Camacho-Hernandez, Gisela Andrea; Salomon, Kristine; Lee, Kuo Hao; Ku, Therese C; Cao, Jianjing; Won, Sung Joon; Friedman, Jacob; Lam, Jenny; Paule, James; Rais, Rana; Klein, Benjamin; Xi, Zheng-Xiong; Shi, Lei; Loland, Claus J; Newman, Amy Hauck.
Afiliación
  • Okorom AV; 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.
  • Camacho-Hernandez GA; 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.
  • Salomon K; Laboratory for Membrane Protein Dynamics, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
  • Lee KH; 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.
  • Ku TC; 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.
  • Cao J; 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.
  • Won SJ; 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.
  • Friedman J; 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.
  • Lam J; Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
  • Paule J; 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.
  • Rais R; Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
  • Klein B; 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.
  • Xi ZX; Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
  • Shi L; Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
  • Loland CJ; 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.
  • Newman AH; 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.
J Med Chem ; 67(1): 709-727, 2024 01 11.
Article en En | MEDLINE | ID: mdl-38117239
ABSTRACT
Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cocaína / Estimulantes del Sistema Nervioso Central Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cocaína / Estimulantes del Sistema Nervioso Central Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos