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In particular, P2X7Rs drive chronic glia-mediated neuroinflammation, which is increasingly recognized as a key contributor to Alzheimer\u2019s disease, a neurodegenerative disorder that lacks effective disease-modifying therapies. Here we identify a potent and selective negative allosteric modulator of P2X7Rs with therapeutic potential. We synthesize a series of small molecules based on a polycyclic scaffold and confirm blood-brain barrier penetration by testing a radiolabeled analogue using positron emission tomography imaging. Through a structure-guided medicinal chemistry campaign centered on our scaffold, we identify four promising P2X7R antagonists. Of these, UB-ALT-P2 exhibits the most favorable safety profile, high oral bioavailability and robust brain penetration. High-resolution cryo-EM structures of UB-ALT-P2 bound to human, mouse, and rat P2X7Rs reveal a conserved antagonist binding mode with steric features that favor prolonged binding to human receptors. In the 5xFAD mouse model of AD, oral UB-ALT-P2 blunts weight loss, improves short- and long-term memory, reduces amyloid-\u03b2 plaque burden, lowers hyperphosphorylated tau, and diminishes oxidative and inflammatory markers. These results establish UB-ALT-P2 as a potent and safe P2X7R antagonist that can mitigate core AD pathologies, providing a compelling foundation for further development.<\/jats:p>","DOI":"10.64898\/2026.04.06.716621","type":"posted-content","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:56:09Z","timestamp":1775753769000},"source":"Crossref","is-referenced-by-count":2,"title":["A brain-penetrant P2X7R antagonist mitigates Alzheimer\u2019s disease pathology"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9732-2249","authenticated-orcid":false,"given":"Andreea L.","family":"Turcu","sequence":"first","affiliation":[{"name":"Laboratori de Qu\u00edmica Farmac\u00e8utica, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, Barcelona, Spain"},{"name":"Institute of Biomedicine of the University of Barcelona, IBUB, Barcelona, 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