Discovery of Selective Inhibitors of Na_V1.7 Templated on Saxitoxin as Therapeutics for Pain.

ABSTRACT: The voltage-gated sodium channel isoform Na_V1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal muscle and the heart, poses a significant challenge to the development of small molecule inhibitors of Na_V1.7. Most inhibitors of Na_V1.7 disclosed to date belong to a class of aryl and acyl sulfonamides that preferentially bind to an inactivated conformation of the channel. By taking advantage of a sequence variation unique to primate Na_V1.7 in the extracellular pore of the channel, a series of bis-guanidinium analogues of the natural product, saxitoxin,

SUBMITTER: Pajouhesh H 

PROVIDER: S-EPMC9661704 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature