Selective Ligands and Drug Discovery Targeting the Voltage-Gated Sodium Channel Nav1.7

The voltage-gated sodium (Nav) channel Nav1.7 has been the focus of intense investigation in recent years. Human genetics studies of individuals with gain-of-function and loss-of-function mutations in the Nav1.7 channel have implicated Nav1.7 as playing a critical role in pain. Therefore, selective inhibition of Nav1.7 represents a potentially new analgesic strategy that is expected to be devoid of the significant liabilities associated with available treatment options. Although the identification and development of selective Nav channel modulators have historically been challenging, a number of recent publications has demonstrated progression of increasingly subtype-selective small molecules and peptides toward potential use in preclinical or clinical studies. In this respect, we focus on three binding sites that appear to offer the highest potential for the discovery and optimization of Nav1.7-selective inhibitors: the extracellular vestibule of the pore, the extracellular loops of voltage-sensor domain II (VSD2), and the extracellular loops of voltage-sensor domain IV (VSD4). Notably, these three receptor sites on Nav1.7 can all be defined as extracellular druggable sites, suggesting that non-small molecule formats are potential therapeutic options. In this chapter, we will review specific considerations and challenges underlying the identification and optimization of selective, potential therapeutics targeting Nav1.7 for chronic pain indications.