Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Bioorganic Chemistry Année : 2021

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

Florian Jacquot
  • Fonction : Auteur
Grzegorz Satała
  • Fonction : Auteur
Sylvain Lamoine
  • Fonction : Auteur
Andrzej Bojarski
Alain Eschalier
  • Fonction : Auteur
Philippe Marin
Christine Courteix

Résumé

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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hal-03324439 , version 1 (24-08-2021)

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Marcin Drop, Florian Jacquot, Vittorio Canale, Séverine Chaumont-Dubel, Maria Walczak, et al.. Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide. Bioorganic Chemistry, 2021, 115, pp.105218. ⟨10.1016/j.bioorg.2021.105218⟩. ⟨hal-03324439⟩
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