Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT(3) and 5-HT(6) Receptor Antagonist with Antipsychotic and Procognitive Properties

[Image: see text] In line with recent clinical trials demonstrating that ondansetron, a 5-HT(3) receptor (5-HT(3)R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT(6) receptor (5-HT(6)R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT(3)/5-HT(6)R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT(3)R antagonist and a neutral antagonist 5-HT(6)R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT(6)R inverse agonist SB399885 nor neutral 5-HT(6)R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT(3)R antagonism and 5-HT(6)R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT(3)/5-HT(6) receptors and encourage further studies on dual-acting 5-HT(3)/5-HT(6)R antagonists for the treatment of psychiatric disorders.