1. Design, Synthesis, and Structure–Activity Relationship Studies of a Series of [4-(4-Carboxamidobutyl)]-1-arylpiperazines: Insights into Structural Features Contributing to Dopamine D3 versus D2 Receptor Subtype Selectivity
- Author
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Leah McAleer, Ling Zhai, Maarten E. A. Reith, J. Robert Bostwick, Eunie Cho, Shea McDowell, Guangyan Zhou, Robert R. Luedtke, Subramaniam Ananthan, Judith V. Hobrath, Tamara Antonio, Michelle Taylor, Surendra K. Saini, and Indira Padmalayam
- Subjects
Models, Molecular ,Arrestins ,CHO Cells ,Chemistry Techniques, Synthetic ,Ligands ,Partial agonist ,Piperazines ,Article ,Structure-Activity Relationship ,03 medical and health sciences ,Cricetulus ,0302 clinical medicine ,Dopamine receptor D3 ,Dopamine receptor D2 ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Receptor ,beta-Arrestins ,030304 developmental biology ,0303 health sciences ,Receptors, Dopamine D2 ,Chemistry ,Receptors, Dopamine D3 ,Antagonist ,Rational design ,3. Good health ,Molecular Docking Simulation ,Dopamine D2 Receptor Antagonists ,Biochemistry ,Docking (molecular) ,Drug Design ,Mutation ,Dopamine Antagonists ,Molecular Medicine ,Hydrophobic and Hydrophilic Interactions ,030217 neurology & neurosurgery - Abstract
Antagonist and partial agonist modulators of the dopamine D3 receptor (D3R) have emerged as promising therapeutics for the treatment of substance abuse and neuropsychiatric disorders. However, development of druglike lead compounds with selectivity for the D3 receptor has been challenging because of the high sequence homology between the D3R and the dopamine D2 receptor (D2R). In this effort, we synthesized a series of acylaminobutylpiperazines incorporating aza-aromatic units and evaluated their binding and functional activities at the D3 and D2 receptors. Docking studies and results from evaluations against a set of chimeric and mutant receptors suggest that interactions at the extracellular end of TM7 contribute to the D3R versus D2R selectivity of these ligands. Molecular insights from this study could potentially enable rational design of potent and selective D3R ligands.
- Published
- 2014
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