Dual 5-HT 6 and D 3 Receptor Antagonists in a Group of 1 H -Pyrrolo[3,2- c ]quinolines with Neuroprotective and Procognitive Activity - Université de Montpellier Accéder directement au contenu
Article Dans Une Revue ACS Chemical Neuroscience Année : 2019

Dual 5-HT 6 and D 3 Receptor Antagonists in a Group of 1 H -Pyrrolo[3,2- c ]quinolines with Neuroprotective and Procognitive Activity

Katarzyna Grychowska
Paulina Koczurkiewicz
  • Fonction : Auteur
Caroline Deville
  • Fonction : Auteur
Martyna Krawczyk
  • Fonction : Auteur
Wojciech Pietruś
  • Fonction : Auteur
Grzegorz Satała
  • Fonction : Auteur
Kamil Piska
  • Fonction : Auteur
Marcin Drop
  • Fonction : Auteur
Andrzej J Bojarski
  • Fonction : Auteur
Piotr Popik
  • Fonction : Auteur
Philippe Marin
Paweł Zajdel

Résumé

In light of the multifactorial origin of neurodegenerative disorders and some body of evidence indicating that pharmacological blockade of serotonin 5-HT 6 and dopamine D 3 receptors might be beneficial for cognitive decline, we envisioned (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1Hpyrrolo[3,2-c]quinoline (CPPQ), a neutral antagonist of 5-HT 6 R, as a chemical template for designing dual antagonists of 5-HT 6 /D 3 receptors. As shown by in vitro experiments, supported by quantum chemical calculations and molecular dynamic simulations, introducing alkyl substituents at the pyrrolidine nitrogen of CPPQ, fulfilled structural requirements for simultaneous modulation of 5-HT 6 and D 3 receptors. The study identified compound 19 ((S)-1-((3chlorophenyl)sulfonyl)-N-(1-isobutylpyrrolidin-3-yl)-1H-pyrrolo-[3,2-c]quinolin-4-amine), which was classified as a dual 5-HT 6 /D 3 R antagonist (K i(5-HT6) = 27 nM, K i(D3) = 7 nM). Compound 19 behaved as a neutral antagonist at G s signaling and had no influence on receptor-operated, cyclin-dependent kinase 5 (Cdk5)-dependent neurite growth. In contrast to the well characterized 5-HT 6 R antagonist intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage induced by doxorubicin, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an index of cell membrane disruption. This feature is of particular importance considering the involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. Biological results obtained for 19 in in vitro tests, translated into procognitive properties in phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in rats.
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hal-02364291 , version 1 (29-11-2020)

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Katarzyna Grychowska, Séverine Chaumont-Dubel, Rafał Kurczab, Paulina Koczurkiewicz, Caroline Deville, et al.. Dual 5-HT 6 and D 3 Receptor Antagonists in a Group of 1 H -Pyrrolo[3,2- c ]quinolines with Neuroprotective and Procognitive Activity. ACS Chemical Neuroscience, 2019, 10 (7), pp.3183-3196. ⟨10.1021/acschemneuro.8b00618⟩. ⟨hal-02364291⟩
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