Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3 and 5-HT6 Receptor Antagonist with Antipsychotic and Procognitive Properties

In line with recent clinical trials demonstrating that ondansetron, a 5-HT₃ receptor (5-HT₃R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT₆ receptor (5-HT₆R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT₃/5-HT₆R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT₃R antagonist and a neutral antagonist 5-HT₆R 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-HT₆R inverse agonist SB399885 nor neutral 5-HT₆R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT₃R antagonism and 5-HT₆R 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-HT₃/5-HT₆ receptors and encourage further studies on dual-acting 5-HT₃/5-HT₆R antagonists for the treatment of psychiatric disorders.