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Here, we report the design, synthesis, and characterization of novel nNOS inhibitors\n                    <jats:bold>3<\/jats:bold>\n                    and\n                    <jats:bold>4<\/jats:bold>\n                    , incorporating dimethylamino-substituted tail groups to exploit hnNOS-specific peripheral pocket interactions. Both compounds retained sub-20 nM potency against human nNOS with enhanced selectivity over endothelial (hn\/he\u2009&gt;\u20091500-fold) and inducible (hn\/hi\u2009&gt;\u2009229-fold) isoforms. Molecular dynamics simulations and MM-GBSA calculations suggested that hnNOS selectivity arises from a dynamically formed cation-\u03c0 interaction between the terminal amino group and W311(B), which is precluded in heNOS due to the steric hindrance from F105. PAMPA-BBB assays in\u1e0ddicated moderate blood-brain barrier permeability, supporting CNS applications. These findings highlight peripheral pocket interactions as key drivers of isoform selectivity and guide future nNOS inhibitor optimization for neurodegenerative diseases and melanoma.\n                  <\/jats:p>","DOI":"10.1007\/s00044-026-03552-3","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T18:28:04Z","timestamp":1775845684000},"page":"757-764","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamic tail amine interactions drive isoform selectivity for potent human neuronal nitric oxide synthase inhibitors"],"prefix":"10.1007","volume":"35","author":[{"given":"Amardeep","family":"Awasthi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koon Mook","family":"Kang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard B.","family":"Silverman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"3552_CR1","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1042\/bj3570593","volume":"357","author":"WK Alderton","year":"2001","unstructured":"Alderton WK, Cooper CE, Knowles RG. 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