{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:14:38Z","timestamp":1792059278550,"version":"4.4.0"},"reference-count":99,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Na+\/Ca2+ exchangers (NCXs) are membrane transporters crucial for calcium homeostasis in excitable tissues, particularly in the central nervous system. Growing evidence indicates that NCX dysfunction contributes to calcium overload and neuronal damage in several neurological conditions. Thus, pharmacological modulation of NCX isoforms (NCX1, NCX2, and NCX3) has emerged as a potential therapeutic strategy for disorders such as stroke, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer\u2019s disease (AD), and Parkinson\u2019s disease (PD). However, the identification of selective modulators directed at specific NCX isoforms, or even different splice variants, remains challenging and limits their clinical validation. This Review aims to provide an updated overview of small-molecule NCX modulators, described over the last two decades. Chemical structures, mechanisms of action, and isoform specificity are discussed, along with the most commonly used biological assays for their functional evaluation.<\/jats:p>","DOI":"10.3390\/ijms26188888","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T12:34:03Z","timestamp":1757680443000},"page":"8888","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Druggability of Sodium Calcium Exchanger (NCX): Challenges and Recent Development"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4282-2788","authenticated-orcid":false,"given":"Antonia","family":"Scognamiglio","sequence":"first","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-156X","authenticated-orcid":false,"given":"Angela","family":"Corvino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Caliendo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7357-5751","authenticated-orcid":false,"given":"Ferdinando","family":"Fiorino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. 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