1. Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide
- Author
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Gilles Subra, Maciej Pawłowski, Paweł Zajdel, Marcin Drop, Kamil Piska, Philippe Marin, Jean Martinez, Florian Jacquot, Alain Eschalier, Andrzej J. Bojarski, Karolina Słoczyńska, Vittorio Canale, Christine Courteix, Gilbert Umuhire Mahoro, Grzegorz Satała, Klaudia Nosalska, Xavier Bantreil, Nicolas Masurier, Elżbieta Pękala, Sylvain Lamoine, Séverine Chaumont-Dubel, Maria Walczak, Frédéric Lamaty, 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), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), 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), Jagiellonian University - Medical College, ANR-17-CE16-0010,Sero6Dev,Réseau de signalisation associé au récepteur 5-HT6 et développement neuronal(2017), ANR-17-CE16-0013,StopSero6TOR,La signalisation mTOR induite par le récepteur 5-HT6 comme cible thérapeutique pour prévenir l'apparition des déficits cognitifs dans la schizophrénie(2017), ANR-19-CE18-0018,SERO6Pain,Les voies de signalisation du récepteur 5-HT6: de nouvelles cibles pour le traitement de la douleur neuropathique?(2019), ANR-18-CE18-0018,SMARt-TB,Molécules de réversion de la résistance aux prodrogues chez M. tberculosis(2018), and 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)
- Subjects
Cdk5 signaling ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Analgesic ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Pharmacology ,Neuropathic pain ,Biochemistry ,5-HT(6) receptor inverse agonism ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Inverse agonist ,Receptor ,Flow chemistry ,Molecular Biology ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,ADME ,0303 health sciences ,Chemistry ,Organic Chemistry ,3. Good health ,Spinal nerve ligation ,mTOR kinase ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,5-HT6 receptor ,Signal transduction ,030217 neurology & neurosurgery - Abstract
International audience; The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT6R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Nonphysiological activation of mTOR kinase by constitutively active 5-HT6R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT6R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT6R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats.
- Published
- 2021
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