Antinociceptive properties of an isoform-selective inhibitor of Nav1.7 derived from saxitoxin in mouse models of pain

Abstract The voltage-gated sodium channel Na v 1.7 is highly expressed in nociceptive afferents and is critically involved in pain signal transmission. Na v 1.7 is a genetically validated pain target in humans because loss-of-function mutations cause congenital insensitivity to pain and gain-of-function mutations cause severe pain syndromes. Consequently, pharmacological inhibition has been investigated as an analgesic therapeutic strategy. We describe a small molecule Na v 1.7 inhibitor, ST-2530, that is an analog of the naturally occurring sodium channel blocker saxitoxin. When evaluated against human Na v 1.7 by patch-clamp electrophysiology using a protocol that favors the resting state, the K d of ST-2530 was 25 ± 7 nM. ST-2530 exhibited greater than 500-fold selectivity over human voltage-gated sodium channel isoforms Na v 1.1–Na v 1.6 and Na v 1.8. Although ST-2530 had lower affinity against mouse Na v 1.7 (K d = 250 ± 40 nM), potency was sufficient to assess analgesic efficacy in mouse pain models. A 3-mg/kg dose administered subcutaneously was broadly analgesic in acute pain models using noxious thermal, mechanical, and chemical stimuli. ST-2530 also reversed thermal hypersensitivity after a surgical incision on the plantar surface of the hind paw. In the spared nerve injury model of neuropathic pain, ST-2530 transiently reversed mechanical allodynia. These analgesic effects were demonstrated at doses that did not affect locomotion, motor coordination, or olfaction. Collectively, results from this study indicate that pharmacological inhibition of Na v 1.7 by a small molecule agent with affinity for the resting state of the channel is sufficient to produce analgesia in a range of preclinical pain models.