{"id":13525,"date":"2024-01-09T06:46:23","date_gmt":"2024-01-09T06:46:23","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13525"},"modified":"2024-01-19T06:46:41","modified_gmt":"2024-01-19T06:46:41","slug":"2024-pharmacologic-characterization-of-ltgo-33-a-selective-small-molecule-inhibitor-of-the-voltage-gated-sodium-channel-nav1-8-with-a-unique-mechanism-of-action","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2024-pharmacologic-characterization-of-ltgo-33-a-selective-small-molecule-inhibitor-of-the-voltage-gated-sodium-channel-nav1-8-with-a-unique-mechanism-of-action\/","title":{"rendered":"2024 &#8211; Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel NaV1.8 with a Unique Mechanism of Action"},"content":{"rendered":"<p id=\"p-1\">Discovery and development of new molecules directed against validated pain targets is required to advance the treatment of pain disorders. Voltage-gated sodium channels (Na<sub>V<\/sub>s) are responsible for action potential initiation and transmission of pain signals. Na<sub>V<\/sub>1.8 is specifically expressed in peripheral nociceptors and has been genetically and pharmacologically validated as a human pain target. Selective inhibition of Na<sub>V<\/sub>1.8 can ameliorate pain while minimizing effects on other Na<sub>V<\/sub>\u00a0isoforms essential for cardiac, respiratory, and central nervous system physiology. Here we present the pharmacology, interaction site, and mechanism of action of LTGO-33, a novel Na<sub>V<\/sub>1.8 small molecule inhibitor. LTGO-33 inhibited Na<sub>V<\/sub>1.8 in the nM potency range and exhibited over 600-fold selectivity against human Na<sub>V<\/sub>1.1-Na<sub>V<\/sub>1.7 and Na<sub>V<\/sub>1.9. Unlike prior reported Na<sub>V<\/sub>1.8 inhibitors that preferentially interacted with an inactivated state via the pore region, LTGO-33 was state-independent with similar potencies against closed and inactivated channels. LTGO-33 displayed species specificity for primate Na<sub>V<\/sub>1.8 over dog and rodent Na<sub>V<\/sub>1.8 and inhibited action potential firing in human dorsal root ganglia neurons. Using chimeras combined with mutagenesis, the extracellular cleft of the second voltage-sensing domain was identified as the key site required for channel inhibition. Biophysical mechanism of action studies demonstrated that LTGO-33 inhibition was relieved by membrane depolarization, suggesting the molecule stabilized the deactivated state to prevent channel opening. LTGO-33 equally inhibited wild-type and multiple Na<sub>V<\/sub>1.8 variants associated with human pain disorders. These collective results illustrate LTGO-33 inhibition via both a novel interaction site and mechanism of action previously undescribed in Na<sub>V<\/sub>1.8 small molecule pharmacologic space.<\/p>\n<p id=\"p-2\"><strong>Significance Statement<\/strong>\u00a0Na<sub>V<\/sub>1.8 sodium channels primarily expressed in peripheral pain-sensing neurons represent a validated target for the development of novel analgesics. Here we present the selective small molecule Na<sub>V<\/sub>1.8 inhibitor LTGO-33 that interdicts a distinct site in a voltage-sensor domain to inhibit channel opening. These results inform the development of new analgesics for pain disorders.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,76],"therapeutic_areas":[56],"target_categories":[61],"target_families":[332],"targets":[93,116,117,141,212,234,236,244,263],"resource_keyword":[],"class_list":["post-13525","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-drug-discovery","therapeutic_areas-pain","target_categories-voltage-gated-ion-channels","target_families-nav-channels","targets-nav1-5","targets-nav1-7","targets-nav1-8","targets-nav1-9","targets-nav1-2","targets-nav1-1","targets-nav1-3","targets-nav1-6","targets-nav1-4"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/13525","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=13525"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=13525"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=13525"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=13525"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=13525"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=13525"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=13525"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=13525"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=13525"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}