Revised Pharmacophore Model for 5-HT2A Receptor Antagonists Derived from the Atypical Antipsychotic Agent Risperidone
| Autor: | José L. Moreno, Urjita H. Shah, Richard A. Glennon, Javier González-Maeso, Supriya A Gaitonde, Malgorzata Dukat |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Risperidone Physiology medicine.drug_class Chemistry Stereochemistry Cognitive Neuroscience Antagonist Atypical antipsychotic Cell Biology General Medicine Receptor antagonist Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Docking (molecular) medicine Pharmacophore Isoxazole Receptor 030217 neurology & neurosurgery 030304 developmental biology medicine.drug |
| Zdroj: | ACS Chemical Neuroscience. 10:2318-2331 |
| ISSN: | 1948-7193 |
| Popis: | Pharmacophore models for 5-HT2A receptor antagonists consist of two aromatic/hydrophobic regions at a given distance from a basic amine. We have previously shown that both aromatic/hydrophobic moieties are unnecessary for binding or antagonist action. Here, we deconstructed the 5-HT2A receptor antagonist/serotonin-dopamine antipsychotic agent risperidone into smaller structural segments that were tested for 5-HT2A receptor affinity and function. We show, again, that the entire risperidone structure is unnecessary for retention of affinity or antagonist action. Replacement of the 6-fluoro-3-(4-piperidinyl)-1,2-benz[ d]isoxazole moiety by isosteric tryptamines resulted in retention of affinity and antagonist action. Additionally, 3-(4-piperidinyl)-1,2-benz[ d]isoxazole (10), which represents less than half the structural features of risperidone, retains both affinity and antagonist actions. 5-HT2A receptor homology modeling/docking studies suggest that 10 binds in a manner similar to risperidone and that there is a large cavity to accept various N4-substituted analogues of 10 such as risperidone and related agents. Alterations of this "extended" moiety improve receptor binding and functional potency. We propose a new risperidone-based pharmacophore for 5-HT2A receptor antagonist action. |
| Databáze: | OpenAIRE |
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