2-Phenyl-1 H -pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT 6 Receptor Inverse Agonists with Cognition-Enhancing Activity
| Autor: | Xavier Bantreil, Anna Gwizdak, Gilles Subra, Joanna Golebiowska, Marcin Drop, Vittorio Canale, Jean Martinez, Gniewomir Latacz, Frédéric Lamaty, Paweł Zajdel, Andrzej J. Bojarski, Rafał Kurczab, Katarzyna Grychowska, Maciej Pawłowski, Piotr Popik, Séverine Chaumont-Dubel, Philippe Marin, Martyna Krawczyk, Maria Walczak, Agnieszka Nikiforuk, Paulina Koczurkiewicz-Adamczyk, Grzegorz Satała |
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| Přispěvatelé: | KARLI, Mélanie, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cdk5 signaling
Metrics & More Article Recommendations Cognition Physiology medicine.drug_class Cognitive Neuroscience inverse agonism Carboxamide Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cognition [CHIM] Chemical Sciences medicine 5-HT 6 receptor Inverse agonist [CHIM]Chemical Sciences Receptor 2-phenyl-1H-pyrrole-3-carboxamide constitutive activity 5-HT receptor 030304 developmental biology 0303 health sciences Quinoline Cell Biology General Medicine attentional set shifting task chemistry 5-HT6 receptor novel object recognition test Serotonin Signal transduction Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | ACS Chemical Neuroscience ACS Chemical Neuroscience, 2021, 12 (7), pp.1228-1240. ⟨10.1021/acschemneuro.1c00061⟩ ACS Chemical Neuroscience, American Chemical Society (ACS), 2021, 12 (7), pp.1228-1240. ⟨10.1021/acschemneuro.1c00061⟩ |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.1c00061⟩ |
| Popis: | International audience; Serotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound's activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists. |
| Databáze: | OpenAIRE |
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