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

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

  • Bioorg Chem. 2021 Oct:115:105218. doi: 10.1016/j.bioorg.2021.105218.
Marcin Drop 1,  Florian Jacquot 2,  Vittorio Canale 3,  Severine Chaumont-Dubel 4,  Maria Walczak 3,  Grzegorz Satała 5,  Klaudia Nosalska 3,  Gilbert Umuhire Mahoro 6,  Karolina Słoczyńska 3,  Kamil Piska 3,  Sylvain Lamoine 2,  Elżbieta Pękala 3,  Nicolas Masurier 6,  Andrzej J Bojarski 5,  Maciej Pawłowski 3,  Jean Martinez 6,  Gilles Subra 6,  Xavier Bantreil 6,  Frédéric Lamaty 6,  Alain Eschalier 2,  Philippe Marin 4,  Christine Courteix 2,  Paweł Zajdel 7
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland; IBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, France.
  • 2 Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France.
  • 3 Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.
  • 4 Institut de Génomique Fonctionelle, Université de Montpellier, CNRS INSERM, 34094 Montpellier, France.
  • 5 Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-343 Kraków, Poland.
  • 6 IBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, France.
  • 7 Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland. Electronic address: pawel.zajdel@uj.edu.pl.
PMID: 34365058 DOI: 10.1016/j.bioorg.2021.105218
Abstract

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. Non-physiological 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.

Keywords

5-HT(6) receptor inverse agonism; Cdk5 signaling; Flow chemistry; Neuropathic pain; Spinal nerve ligation; mTOR kinase.

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