| First Author | Bankar G | Year | 2018 |
| Journal | Cell Rep | Volume | 24 |
| Issue | 12 | Pages | 3133-3145 |
| PubMed ID | 30231997 | Mgi Jnum | J:271208 |
| Mgi Id | MGI:6278466 | Doi | 10.1016/j.celrep.2018.08.063 |
| Citation | Bankar G, et al. (2018) Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain. Cell Rep 24(12):3133-3145 |
| abstractText | Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma. |
