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

Paweł Zajdel (1) , Katarzyna Grychowska (1) , Szczepan Mogilski (1) , Rafał Kurczab (2) , Grzegorz Satała (2) , Ryszard Bugno (2) , Tomasz Kos (2) , Joanna Gołębiowska (2) , Natalia Malikowska-Racia (2) , Agnieszka Nikiforuk (2) , Séverine Chaumont-Dubel (3) , Xavier Bantreil (4) , Maciej Pawłowski (1) , Jean Martinez (4) , Gilles Subra (4) , Frédéric Lamaty (4) , Philippe Marin (3) , Andrzej Bojarski (2) , Piotr Popik (2)

1 UJ - Uniwersytet Jagielloński w Krakowie = Jagiellonian University
2 PAN - Polska Akademia Nauk = Polish Academy of Sciences = Académie polonaise des sciences
3 IGF - Institut de Génomique Fonctionnelle
4 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

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.

Domaines: Chimie thérapeutique

Paweł Zajdel, Katarzyna Grychowska, Szczepan Mogilski, Rafał Kurczab, Grzegorz Satała, et al.. Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT 3 and 5-HT 6 Receptor Antagonist with Antipsychotic and Procognitive Properties. Journal of Medicinal Chemistry, 2021, 64 (18), pp.13279-13298. ⟨10.1021/acs.jmedchem.1c00224⟩. ⟨hal-03357806⟩