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Despite its relevance, there is no selective antagonist useful in the treatment of diseases related to this receptor. In this context, research for a selective, safe, and potent antagonist compound that can be used in clinical therapy has been growing. In this work, we evaluated the potential antagonistic activity of three fungal extracts, namely, <jats:italic>Vishniacozyma victoriae<\/jats:italic>, <jats:italic>Metschnikowia australis<\/jats:italic>, and <jats:italic>Ascomycota<\/jats:italic> sp., which were discovered in a high\u2010throughput screening campaign to search for new antagonists for P2X7R from natural products. First, the IC<jats:sub>50<\/jats:sub> values of these fungal extracts were determined in J774.G8 (murine macrophage cell line) and U937 (human monocyte cell line) cells through dye uptake assays. The IC<jats:sub>50<\/jats:sub> values of <jats:italic>V.\u00a0victoriae<\/jats:italic> were 2.6 and 0.92\u00a0\u03bcg\/mL, <jats:italic>M.\u00a0australis<\/jats:italic> has IC<jats:sub>50<\/jats:sub> values of 3.8 and 1.5\u00a0\u03bcg\/mL, and <jats:italic>Ascomycota<\/jats:italic> sp. showed values of 2.1 and 0.67\u00a0\u03bcg\/mL in J774.G8 and U937 cells, respectively. These extracts also significantly inhibited propidium\u00a0iodide and Lucifer yellow uptake via P2X7R pore, P2X7R currents in electrophysiology, IL\u20101\u03b2 release, and the production of oxide nitric and reactive oxygen species. The extracts did not cause cytotoxicity within a period of 24\u00a0h. The results showed the promising antagonistic activity of these extracts toward P2X7R, thereby indicating that they can be future candidates for phytomedicines with potential clinical applicability.<\/jats:p>","DOI":"10.1002\/ptr.6412","type":"journal-article","created":{"date-parts":[[2019,7,2]],"date-time":"2019-07-02T08:50:15Z","timestamp":1562057415000},"page":"2319-2328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A new insight into purinergic pharmacology: Three fungal species as natural P2X7R antagonists"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-2869","authenticated-orcid":false,"given":"R\u00f4mulo Jos\u00e9","family":"Soares\u2010Bezerra","sequence":"first","affiliation":[{"name":"Laboratory of Cellular Communication, Oswaldo Cruz Institute Oswaldo Cruz Foundation  Rio de Janeiro 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