In silico and pharmacological study of N,S-acetal juglone derivatives as inhibitors of the P2X7 receptor-promoted in vitro and in vivo inflammatory response

• Published in: Biomedicine & pharmacotherapy Vol. 162; p. 114608
• Main Authors: Pacheco, Paulo Anastácio Furtado, Faria, Juliana Vieira, Silva, Ana Cláudia, von Ranke, Natalia Lidmar, Silva, Robson Coutinho, Rodrigues, Carlos Rangel, da Rocha, David Rodrigues, Faria, Robson Xavier
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.06.2023; Elsevier
• Subjects: Acetals; Adenosine Triphosphate - metabolism; ATP; Drug; Humans; Inflammation; Naphthoquinone; Naphthoquinones; P2X7R; Purinergic receptors; Receptors, Purinergic P2X7; Drug; Inflammation; Purinergic receptors; ATP; P2X7R; Naphthoquinone
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114608

Purinergic receptors are transmembrane proteins responsive to extracellular nucleotides and are expressed by several cell types throughout the human body. Among all identified subtypes, the P2×7 receptor has emerged as a relevant target for the treatment of inflammatory disease. Several clinical trials have been conducted to evaluate the effectiveness of P2×7R antagonists. However, to date, no selective antagonist has reached clinical use. In this work, we report the pharmacological evaluation of eleven N, S-acetal juglone derivatives as P2×7R inhibitors. Using in vitro assays and in vivo experimental models, we identified one derivative with promising inhibitory activity and low toxicity. Our in silico studies indicate that the 1,4-naphthoquinone moiety might be a valuable molecular scaffold for the development of novel P2×7R antagonists, as suggested by our previous studies. [Display omitted] •P2X7 receptor (P2X7R) is an ATP-gated ion channel involved in several inflammatory diseases and neuropathic pain.•P2X7R activation triggers several pro-inflammatory mechanisms, such as NLRP3 inflammasome assembly and release of IL-1β.•Despite the key role of P2X7R in inflammatory disorders, no inhibitor is approved for clinical use yet.•Juglone-derived N,S-acetal compounds showed good in vitro and in vivo P2X7R inhibitory activity.•In silico studies corroborates that 1,4-naphthoquinones might be valuable synthetic platforms for novel P2X7 antagonists.