Reformulating a Pharmacophore for 5-HT2A Serotonin Receptor Antagonists
| Autor: | Kelsey S. Hideshima, Diomedes E. Logothetis, Jose M. Eltit, Jason Younkin, Lia Baki, Amr Ellaithy, Supriya A Gaitonde, Javier González-Maeso, Malgorzata Dukat, José L. Moreno, Rakesh H. Vekariya, Sneha Shah, Richard A. Glennon, Peter Drossopoulos |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Serotonin Physiology Stereochemistry Cognitive Neuroscience Voltage clamp Tritium 010402 general chemistry 01 natural sciences Biochemistry Article Calcium in biology Membrane Potentials Xenopus laevis 03 medical and health sciences chemistry.chemical_compound medicine Animals Humans Receptor Serotonin 5-HT2A Receptor 5-HT receptor Risperidone Benzisoxazole Cell Biology General Medicine 0104 chemical sciences HEK293 Cells 030104 developmental biology G Protein-Coupled Inwardly-Rectifying Potassium Channels chemistry Barium Mutation Oocytes Serotonin 5-HT2 Receptor Antagonists Calcium Amine gas treating Ketanserin Serotonin Antagonists Pharmacophore Hydrophobic and Hydrophilic Interactions Protein Binding medicine.drug |
| Zdroj: | ACS Chemical Neuroscience. 7:1292-1299 |
| ISSN: | 1948-7193 |
| Popis: | Several pharmacophore models have been proposed for 5-HT2A serotonin receptor antagonists. These typically consist of two aromatic/hydrophobic moieties separated by a given distance from each other, and from a basic amine. Although specified distances might vary, the models are relatively similar in their general construction. Because our preliminary data indicated that two aromatic (hydrophobic) moieties might not be required for such action, we deconstructed the serotonin-dopamine antipsychotic agent risperidone (1) into four smaller structural fragments that were thoroughly examined in 5-HT2A receptor binding and functional (i.e., two-electrode voltage clamp (TEVC) and intracellular calcium release) assays. It was apparent that truncated risperidone analogues behaved as antagonists. In particular, 6-fluoro-3-(1-methylpiperidin-4-yl)benzisoxazole (4) displayed high affinity for 5-HT2A receptors (Ki of ca. 12 nM) relative to risperidone (Ki of ca. 5 nM) and behaved as a potent 5-HT2A serotonin receptor antagonist. These results suggest that multiple aromatic (hydrophobic) moieties are not essential for high-affinity 5-HT2A receptor binding and antagonist activity and that current pharmacophore models for such agents are very much in need of revision. |
| Databáze: | OpenAIRE |
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