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

  • J Med Chem. 2021 Sep 23;64(18):13279-13298. doi: 10.1021/acs.jmedchem.1c00224.
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 J Bojarski  2 ,  Piotr Popik  2
Affiliations
  • 1. Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.
  • 2. Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-343 Kraków, Poland.
  • 3. Institut de Génomique Fonctionelle, Université de Montpellier, CNRS, INSERM, 34094 Montpellier, France.
  • 4. IBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, France.
PMID: 34467765 DOI: 10.1021/acs.jmedchem.1c00224
Abstract

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.

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