Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues
| Autor: | Jonathan L. Katz, Claus J. Loland, Lei Shi, Theresa A. Kopajtic, Jianjing Cao, Amy Hauck Newman, Oluyomi M. Okunola-Bakare |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Stereochemistry Thio Modafinil Thioacetamide Article Rats Sprague-Dawley Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Dopamine Amide Chlorocebus aethiops mental disorders Drug Discovery medicine Animals Benzhydryl Compounds Serotonin transporter Dopamine transporter Serotonin Plasma Membrane Transport Proteins Dopamine Plasma Membrane Transport Proteins Binding Sites Norepinephrine Plasma Membrane Transport Proteins Trifluoromethyl biology Brain Stereoisomerism Rats Molecular Docking Simulation chemistry COS Cells Mutation biology.protein Molecular Medicine Amine gas treating Acetamide Protein Binding medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm401754x |
| Popis: | 2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (±)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (±)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (±)-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. |
| Databáze: | OpenAIRE |
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