637000-19-2Relevant articles and documents
Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3and 5-HT6Receptor Antagonist with Antipsychotic and Procognitive Properties
Zajdel, Pawe?,Grychowska, Katarzyna,Mogilski, Szczepan,Kurczab, Rafa?,Sata?a, Grzegorz,Bugno, Ryszard,Kos, Tomasz,Go?e?biowska, Joanna,Malikowska-Racia, Natalia,Nikiforuk, Agnieszka,Chaumont-Dubel, Séverine,Bantreil, Xavier,Paw?owski, Maciej,Martinez, Jean,Subra, Gilles,Lamaty, Frédéric,Marin, Philippe,Bojarski, Andrzej J.,Popik, Piotr
supporting information, p. 13279 - 13298 (2021/09/20)
In line with recent clinical trials demonstrating that ondansetron, a 5-HT3receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compoundFPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway.FPPQshows selectivity over 87 targets and decent brain penetration. Likewise,FPPQinhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast toFPPQ, 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 byFPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.
