Design, synthesis and structure-activity relationship studies of hexahydropyrazinoquinolines as a novel class of potent and selective dopamine receptor 3 (D3) ligands |
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Authors: | Ji Min Chen Jianyong Ding Ke Wu Xihan Varady Judith Levant Beth Wang Shaomeng |
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Institution: | Department of Internal Medicine, University of Michigan, CCGC/3316, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0934, USA. |
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Abstract: | A hexahydropyrazinoquinoline (compound 5c) was previously discovered as a novel D3 ligand with a moderate binding affinity to the D3 receptor (Ki=304 nM) but no selectivity over the D1-like and D2-like receptors. In this study, we wish to report the design, synthesis and structure-activity relationship studies of a series of novel hexahydropyrazinoquinolines. Our efforts resulted in new compounds with improved binding affinity and selectivity. Among them, compound 12d has a Ki value of 2.6 nM for its binding affinity to the D3 receptor and has >2000- and 99-fold selectivity over the D1-like and D2-like receptors, respectively, representing a potent and selective D3 ligand. |
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