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Genetic gain-of-function and loss-of-function Na\n                    <jats:sub>V<\/jats:sub>\n                    1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate Na\n                    <jats:sub>V<\/jats:sub>\n                    1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting Na\n                    <jats:sub>V<\/jats:sub>\n                    1.7 have been advanced to clinical development, no Na\n                    <jats:sub>V<\/jats:sub>\n                    1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a Na\n                    <jats:sub>V<\/jats:sub>\n                    1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 72\u00a0nM and greater than 200-fold selectivity over off-target sodium channel isoforms, Na\n                    <jats:sub>V<\/jats:sub>\n                    1.1\u20131.6 and Na\n                    <jats:sub>V<\/jats:sub>\n                    1.8. In contrast to other Na\n                    <jats:sub>V<\/jats:sub>\n                    1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting Na\n                    <jats:sub>V<\/jats:sub>\n                    1.7.\n                  <\/jats:p>","DOI":"10.1038\/s41598-020-71135-2","type":"journal-article","created":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T07:26:39Z","timestamp":1599722799000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Discovery of a selective, state-independent inhibitor of NaV1.7 by modification of guanidinium toxins"],"prefix":"10.1038","volume":"10","author":[{"given":"H.","family":"Pajouhesh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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