Discovery of a Selective, State-Independent Inhibitor of Na_V1.7 by Modification of Guanidinium Toxins

Abstract

The voltage-gated sodium channel isoform NaV1.7 is highly expressed in small diameter dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gainof-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These 20 35 addiction. Voltage-gated sodium ion channels (NaVs) have emerged as promising targets for the development of non-opioid pain medicines. NaVs are involved in the propagation of electrical signals along neurons throughout the body. Humans born without a functional copy of one sodium channel subtype, NaV1.7, are unable to experience most types of pain. In the present work, we disclose the discovery and characterization of a selective inhibitor of NaV1.7 that reduces 40 sensitivity to a painful thermal stimulus in non-human primates. Findings from this work may help guide the development of novel, non-addictive drug candidates as alternatives to opioids.

Chemical and Biological Tools for the Study of Voltage‐Gated Sodium Channels in Electrogenesis and Nociception

“…Alternative sulfonamide‐based ligands are also reported to be highly selective, state‐dependent Na V inhibitors, with AM0466 and AM‐8379 exhibiting 100‐ to 1000‐fold affinity for Na V 1.7 over any other isoform [178–181] . Recently, SiteOne Therapeutics has disclosed a first‐in‐class, state‐independent Na V 1.7‐selective inhibitor, ST‐2262, modeled after the natural product saxitoxin [182] . This work demonstrates the potential for targeting the outer vestibule of the channel pore to achieve isoform specificity.…”