The voltage gated sodium channel Nav1.7 is highly expressed in nociceptive afferents and is critically involved in pain signal transmission. Nav1.7 is a genetically validated pain target in humans, as 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 Nav1.7 inhibitor, ST-2530, that is an analog of the naturally occurring sodium channel blocker saxitoxin. When evaluated against human Nav1.7 by patch clamp electrophysiology using a protocol that favors the resting state, the Kd of ST-2530 was 25 ± 7 nM. ST-2530 exhibited greater than 500-fold selectivity over human voltage gated sodium channel isoforms Nav1.1-Nav1.6 and Nav1.8. While ST-2530 had lower affinity against mouse Nav1.7 (Kd = 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 employing noxious thermal, mechanical, and chemical stimuli. ST-2530 also reversed thermal hypersensitivity following 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 the present study indicate that pharmacological inhibition of Nav1.7 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.

References

PubMed