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
  • 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: [email protected].
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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