2. Academic Validation
  3. 1,4-Naphthoquinones potently inhibiting P2X7 receptor activity

1,4-Naphthoquinones potently inhibiting P2X7 receptor activity

  • Eur J Med Chem. 2018 Jan 1:143:1361-1372. doi: 10.1016/j.ejmech.2017.10.033.
R X Faria 1,  F H Oliveira 2,  J P Salles 2,  A S Oliveira 2,  N L von Ranke 3,  M L Bello 4,  C R Rodrigues 4,  H C Castro 5,  A R Louvis 6,  D L Martins 6,  V F Ferreira 7
Affiliations

Affiliations

  • 1 Laboratório de Toxoplasmose e outras protozooses, Instituto Oswaldo Cruz, Fiocruz, Brazil. Electronic address: robson.xavier@gmail.com.
  • 2 Laboratório de Toxoplasmose e outras protozooses, Instituto Oswaldo Cruz, Fiocruz, Brazil.
  • 3 Programa de Pós-graduação em Ciências e Biotecnologia, Universidade Federal Fluminense, Campus do Valonguinho, Centro, Niterói, RJ 24020-141, Brazil; Laboratório de Modelagem Molecular e QSAR, Departamento de Fármacos e Medicamentos, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, CEP 21941-902 RJ, Brazil.
  • 4 Laboratório de Modelagem Molecular e QSAR, Departamento de Fármacos e Medicamentos, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, CEP 21941-902 RJ, Brazil.
  • 5 Programa de Pós-graduação em Ciências e Biotecnologia, Universidade Federal Fluminense, Campus do Valonguinho, Centro, Niterói, RJ 24020-141, Brazil.
  • 6 Grupo de Pesquisas em Catálise e Síntese, Laboratório 413, Universidade Federal Fluminense, Instituto de Química, Campus do Valonguinho, Centro, Niterói, RJ 24020-141, Brazil.
  • 7 Universidade Federal Fluminense, Departamento de Química Orgânica, Instituto de Química, Campus do Valonguinho, Niterói, RJ CEP 24020-150, Brazil.
PMID: 29133043 DOI: 10.1016/j.ejmech.2017.10.033
Abstract

P2X7 Receptor (P2X7R) is an ATP-gated ion-channel with potential therapeutic applications. In this study, we prepared and searched a series of 1,4-naphthoquinones derivatives to evaluate their antagonistic effect on both human and murine P2X7 receptors. We explored the structure-activity relationship and binding mode of the most active compounds using a molecular modeling approach. Biological analysis of this series (eight analogues and two compounds) revealed significant in vitro inhibition against both human and murine P2X7R. Further characterization revealed that AN-03 and AN-04 had greater potency than BBG and A740003 in inhibiting dye uptake, IL-1β release, and carrageenan-induced paw edema in vivo. Moreover, we used electrophysiology and molecular docking analysis for characterizing AN-03 and AN-04 action mechanism. These results suggest 1,4-napthoquinones, mainly AN-04, as potential leads to design new P2X7R blockers and anti-inflammatory drugs.

Keywords

Dye uptake; IL-1β release; Molecular docking; Naphthoquinones; P2X7 receptor; Paw edema.

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