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

Authors
  • Zajdel, Paweł1
  • Grychowska, Katarzyna1
  • Mogilski, Szczepan1
  • Kurczab, Rafał2
  • Satała, Grzegorz2
  • Bugno, Ryszard2
  • Kos, Tomasz2
  • Gołębiowska, Joanna2
  • Malikowska-Racia, Natalia2
  • Nikiforuk, Agnieszka2
  • Chaumont-Dubel, Séverine3
  • Bantreil, Xavier4
  • Pawłowski, Maciej1
  • Martinez, Jean4
  • Subra, Gilles4
  • Lamaty, Frédéric4
  • Marin, Philippe3
  • Bojarski, Andrzej J.2
  • Popik, Piotr2
  • 1 Jagiellonian University Medical College, Poland , (Poland)
  • 2 Maj Institute of Pharmacology, Polish Academy of Sciences, Poland , (Poland)
  • 3 Institut de Génomique Fonctionelle, Université de Montpellier, CNRS, INSERM, France , (France)
  • 4 IBMM, Université de Montpellier, CNRS, ENSCM, France , (France)
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Sep 01, 2021
Volume
64
Issue
18
Pages
13279–13298
Identifiers
DOI: 10.1021/acs.jmedchem.1c00224
PMID: 34467765
PMCID: PMC8474115
Source
PubMed Central
Disciplines
  • Article
License
Unknown

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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