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Reformulating a Pharmacophore for 5-HT2A Serotonin Receptor Antagonists.

Abstract：

: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.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Younkin J,Gaitonde SA,Ellaithy A,Vekariya R,Baki L,Moreno JL,Shah S,Drossopoulos P,Hideshima KS,Eltit JM,González-Maeso J,Logothetis DE,Dukat M,Glennon RA

doi

10.1021/acschemneuro.6b00162

subject

Has Abstract

pub_date

2016-09-21 00:00:00

pages

1292-9

issue

9

issn

1948-7193

journal_volume

7

pub_type

杂志文章

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