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Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide

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Drop, Marcin | Jacquot, Florian | Canale, Vittorio | Chaumont-Dubel, Séverine | Walczak, Maria | Satała, Grzegorz | Nosalska, Klaudia | Mahoro, Gilbert Umuhire | Słoczyńska, Karolina | Piska, Kamil | Lamoine, Sylvain | Pękala, Elżbieta | Masurier, Nicolas | Bojarski, Andrzej | Pawłowski, Maciej | Martinez, Jean | Subra, Gilles | Bantreil, Xavier | Lamaty, Frédéric | Eschalier, Alain | Marin, Philippe | Courteix, Christine | Zajdel, Paweł

Edité par CCSD ; Elsevier -

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.

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