Author | Martins, Daniela de Luna | |
Author | Borges, Adriel Alves | |
Author | Silva, Nayane A. do A. e | |
Author | Faria, Juliana Vieira | |
Author | Hoelz, Lucas Villas Bôas | |
Author | Souza, Hellen Valério Chaves Moura de | |
Author | Bello, Murilo Lamim | |
Author | Boechat, Nubia | |
Author | Ferreira, Vitor Francisco | |
Author | Faria, Robson Xavier | |
Access date | 2021-02-19T19:47:12Z | |
Available date | 2021-02-19T19:47:12Z | |
Document date | 2020 | |
Citation | MARTINS, Daniela de Luna et al. P2X7 receptor inhibition by 2-amino-3-aryl-1,4-naphthoquinones. Biorganic Chemistry, v. 104, p. 1-11, Sept. 2020. | pt_BR |
ISSN | 0045-2068 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/46113 | |
Language | eng | pt_BR |
Publisher | Elsevier | pt_BR |
Rights | restricted access | pt_BR |
Subject in Portuguese | Quinona | pt_BR |
Subject in Portuguese | Receptor purinérgico | pt_BR |
Subject in Portuguese | Anti-inflamatório | pt_BR |
Subject in Portuguese | Canal de cation | pt_BR |
Subject in Portuguese | Acoplamento suzuki | pt_BR |
Title | P2X7 receptor inhibition by 2-amino-3-aryl-1,4-naphthoquinones | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.bioorg.2020.104278 | |
Abstract | Extracellular ATP activates purinergic receptors such as P2X7, cationic channels for Ca2+, K+, and Na+. There is
robust evidence of the involvement of these receptors in the immune response, so P2X7 receptors (P2X7R) are
considered a potential therapeutic target for the development of anti-inflammatory drugs. Although there are
many studies of the anti-inflammatory properties of naphthoquinones, these molecules have not yet been explored
as P2X7 antagonists. In previous work, our group prepared 3-substituted (halogen or aryl) 2-hydroxy-1,4-
naphthoquinones and studied their action on P2X7R. In this paper, eight 2-amino-3-aryl-1,4-naphthoquinones
were evaluated to identify the inhibitory activity on P2X7R and the toxicological profile. Three analogues (AD-
4CN, AD-4Me, and AD-4F) exhibited reduced toxicity for mammalian cells with CC50 values higher than
500 μM. These three 3-substituted 2-amino-1,4-naphthoquinones inhibited murine P2X7R (mP2X7R) in vitro.
However, the analogues AD-4CN and AD-4Me showed low selectivity index values. AD-4F inhibited both
mP2X7R and human P2X7R (hP2X7R) with IC50 values of 0.123 and 0.93 μM, respectively. Additionally, this
analogue exhibited higher potency than BBG at inhibiting the ATP-induced release of IL-1β in vitro. Carrageenaninduced
paw edema in vivo was reversed for AD-4F with an ID50 value of 11.51 ng/kg. Although AD-4F was less
potent than previous 3-substituted (halogen or aryl) 2-hydroxy-1,4-naphthoquinones such as AN-04 in vitro, this
3-substituted 2-amino-1,4-naphthoquinone revealed higher potency in vivo to reduce the edematogenic response.
In silico analysis suggests that the binding site of the novel 2-amino-3-aryl-1,4-naphthoquinone derivatives,
including all the tautomeric forms, is located in the pore area of the hP2X7R model. Based on these results, we
considered AD-4F to be a satisfactory P2X7R inhibitor. AD-4F might be used as a scaffold structure to design a
novel series of inhibitors with potential inhibitory activity on murine (mP2X7R) and human (hP2X7R) P2X7
receptors. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Química. Grupo de Pesquisa em Catálise e Síntese. Niterói, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Química. Grupo de Pesquisa em Catálise e Síntese. Niterói, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Química. Grupo de Pesquisa em Catálise e Síntese. Niterói, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Biologia. Programa de Pós-Graduação em Ciências e Biotecnologia. Niterói, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxoplasmose e outras Protozooses. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundacao Oswaldo Cruz. Farmanguinhos. Laboratorio de Sintese de Fármacos-LASFAR. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundacao Oswaldo Cruz. Farmanguinhos. Laboratorio de Sintese de Fármacos-LASFAR. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Laboratório de Planejamento Farmacêutico e Simulação Computacional. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundacao Oswaldo Cruz. Farmanguinhos. Laboratorio de Sintese de Fármacos-LASFAR. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Faculdade de Farmácia. Departamento de Tecnologia Farmacêutica. Niterói, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Biologia. Programa de Pós-Graduação em Ciências e Biotecnologia. Niterói, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxoplasmose e outras Protozooses. Rio de Janeiro, RJ, Brasil. | pt_BR |
Subject | Quinone | pt_BR |
Subject | Purinergic receptor | pt_BR |
Subject | Anti-inflammatory | pt_BR |
Subject | Cation channel | pt_BR |
Subject | Suzuki coupling | pt_BR |
Embargo date | 2023-09 | |