Academic Journal
Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5‑HT 3 and 5‑HT 6 Receptor Antagonist with Antipsychotic and Procognitive Properties
| العنوان: | Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5‑HT 3 and 5‑HT 6 Receptor Antagonist with Antipsychotic and Procognitive Properties |
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| المؤلفون: | Paweł Zajdel, Katarzyna Grychowska, Szczepan Mogilski, Rafał Kurczab, Grzegorz Satała, Ryszard Bugno, Tomasz Kos, Joanna Gołębiowska, Natalia Malikowska-Racia, Agnieszka Nikiforuk, Séverine Chaumont-Dubel, Xavier Bantreil, Maciej Pawłowski, Jean Martinez, Gilles Subra, Frédéric Lamaty, Philippe Marin, Andrzej J. Bojarski, Piotr Popik |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Biochemistry, Medicine, Cell Biology, Neuroscience, Physiology, Pharmacology, Cancer, Mental Health, Infectious Diseases, Chemical Sciences not elsewhere classified, rational polypharmacological approach, decent brain penetration, ameliorates cognitive deficits, known procognitive effects, 6 , 3 , displays procognitive properties, 5 ‑ ht, fppq , neutral antagonist 5, procognitive properties, neutral 5, target 5, acting 5, shows selectivity, psychiatric disorders, like symptoms, inhibits phencyclidine, hybridization strategy, gs pathway |
| الوصف: | In line with recent clinical trials demonstrating that ondansetron, a 5-HT 3 receptor (5-HT 3 R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT 6 receptor (5-HT 6 R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT 3 /5-HT 6 R antagonists. We identified the first-in-class compound FPPQ , which behaves as a 5-HT 3 R antagonist and a neutral antagonist 5-HT 6 R 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-HT 6 R inverse agonist SB399885 nor neutral 5-HT 6 R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT 3 R antagonism and 5-HT 6 R 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-HT 3 /5-HT 6 receptors and encourage further studies on dual-acting 5-HT 3 /5-HT 6 R antagonists for the treatment of psychiatric disorders. |
| نوع الوثيقة: | article in journal/newspaper dataset |
| اللغة: | unknown |
| Relation: | https://doi.org/10.1021/acs.jmedchem.1c00224.s001 |
| DOI: | 10.1021/acs.jmedchem.1c00224.s001 |
| الاتاحة: | https://doi.org/10.1021/acs.jmedchem.1c00224.s001 |
| Rights: | undefined |
| رقم الانضمام: | edsbas.1A49920E |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.jmedchem.1c00224.s001 |
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