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Overview
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Background
GX-674 is an aryl sulfonamide class of antagonists that inhibits Nav1.7 [1]
Nav (voltage-gated sodium) channels conduct ionic currents that initiate action potentials in neurons and muscles cells. Human express 9 Nav channel isoforms (Nav 1.1-1.9), among which Nav 1.7 channel are express in olfactory epithelium, sympathetic ganglion, and dorsal root ganglion sensory neurons. Gain-of-function mutations in Nav1.7 are associated with extreme pain disorders whereas loss-of-function mutations cause congenital insensitivity to pain in individuals. [1]
In HEK293 cells, patch clamp analysis was perform for human Nav channels. GX-674 shows potent inhibition effect on Nav.1.7 (IC50= 0.1nM). GX-674 also exhibits substantial selectivity on different Nav subtypes. It shows much higher inhibitory effects on Nav 1.7 over other Nav isoform, such as 100000 times more potent for Nav1.7 than for Nav 1.5. GX-74 is also reported to bind to a high-affinity, isoform-selective, and extracellularly accessible site on VSD4. (i.e. one of the peripheral voltage-sensor domains of Nav.1.7). [1]
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