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We show that natural aminosterols inhibit the NMDAR\u2010mediated increase of intracellular calcium ions in cultured primary neurons and neuroblastoma cells. Structural comparison with known NMDAR\u2010negative allosteric modulators, such as pregnanolone\u2010sulfate\u20102 (PAS), raises the hypothesis that aminosterols have the same mechanism of action. Fluorescence resonance energy transfer (FRET) measurements using labeled NMDAR and the labeled aminosterol trodusquemine (TRO) indicate close spatial proximity, likely arising from binding. Other indirect yet plausible mechanisms for NMDAR inhibition by TRO were excluded. Electrophysiological patch clamp measurements on primary neurons indicate that pre\u2010incubated TRO inhibits NMDA\u2010induced ion currents with a\n                    <jats:italic>IC<\/jats:italic>\n                    <jats:sub>50<\/jats:sub>\n                    of 5\u2009n\n                    <jats:sc>m<\/jats:sc>\n                    . Inhibition is observed only after cell membrane pre\u2010adsorption, indicating accessibility to NMDAR from the cell membrane and binding to the transmembrane domains (TMDs) and TMD\u2010ligand\u2010binding domain (LBD) linkers, similarly to PAS. The TRO IC\n                    <jats:sub>50<\/jats:sub>\n                    is 5000\u2010fold higher than that of PAS and 20\u201316\u2009000 times higher than those of other inhibitors binding to TMD\/TMD\u2010LBD regions, identifying aminosterols as promising and potent NMDAR modulators.\n                  <\/jats:p>","DOI":"10.1111\/febs.70072","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T09:48:23Z","timestamp":1742809703000},"page":"3521-3544","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Natural aminosterols inhibit\n                    <scp>NMDA<\/scp>\n                    receptors with low nanomolar potency"],"prefix":"10.1111","volume":"292","author":[{"given":"Giulia","family":"Fani","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry University of Florence  Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Coppi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology University of Florence  Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Errico","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry University of Florence  Italy"},{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry University of Cambridge  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Cherchi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology University of Florence  Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Gennari","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry University of Florence  Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Barbut","sequence":"additional","affiliation":[{"name":"Enterin Research Institute Inc.  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