Reformulating a Pharmacophore for 5-HT_2A Serotonin Receptor Antagonists

Several pharmacophore models have been proposed for 5-HT_2A 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-HT_2A 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-HT_2A receptors (K_i of ca. 12 nM) relative to risperidone (K_i of ca. 5 nM) and behaved as a potent 5-HT_2A serotonin receptor antagonist. These results suggest that multiple aromatic (hydrophobic) moieties are not essential for high-affinity 5-HT_2A receptor binding and antagonist activity and that current pharmacophore models for such agents are very much in need of revision.