Abstract
The voltage-gated sodium channel isoform NaV1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-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 findings implicate NaV1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting NaV1.7 have been advanced to clinical development, no NaV1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a NaV1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC50 of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, NaV1.1–1.6 and NaV1.8. In contrast to other NaV1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting NaV1.7.
Highlights
The voltage-gated sodium channel isoform NaV1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission
NaV1.7 loss-of-function mutations result in whole-body insensitivity to pain; gain-of-function variants are associated with episodic extreme pain disorders and small fiber n europathies[2,3,4,5]
A major challenge in the pursuit of safe and effective N aV1.7 inhibitors has been the identification of small molecules that are selective over off-target proteins, including other NaV isoforms, to achieve a suitable margin of safety
Summary
The voltage-gated sodium channel isoform NaV1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-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. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting NaV1.7. NaV inhibitors (e.g., bupivacaine, lidocaine, carbamazepine) are both state- and frequency-dependent agents that lodge in the intracellular pore of the α-subunit, a site that is highly conserved between isoforms. These drugs rely on local administration to achieve a margin between the desired pharmacodynamic effect and dose-limiting side effects. A class of small molecule aryl and acyl sulfonamide compounds bind to an activated conformation of VSD IV and prevent
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