Selective targeting of
sodium channel subtypes Nav1.7, Nav1.8, and Nav1.9, preferentially expressed by peripheral nociceptors, represents a unique opportunity to develop
analgesics devoid of central side effects. Several compounds that target Nav1.7 and Nav1.8 with different degrees of selectivity have been developed and are currently being tested in clinical trials for multiple
pain indications. Among these chemicals,
benzothiazole-like compounds emerged as potent
sodium channel blockers. We evaluated the effects of
dexpramipexole, a
benzothiazole-bearing
drug with pleiotypic neuroactive properties and a good safety profile in humans, on
sodium conductances of dorsal root ganglia neurons, as well as in multiple nociceptive and
neuropathic pain models.
Dexpramipexole blocks TTX-resistant
sodium conductances in cultured rat dorsal root ganglion neurons with an IC50 of 294.4 nM, suggesting selectivity towards Nav1.8. In keeping with this,
dexpramipexole does not affect
sodium currents in dorsal root ganglion neurons from Nav1.8 null mice and acquires binding pose predicted to overlap that of the Nav1.8 channel-selective blocker A-8034637. The
drug provides
analgesia when parenterally, orally, or topically applied in inflammatory and visceral mouse
pain models, as well as in mice affected by
neuropathic pain induced by
oxaliplatin, nerve constriction, or diabetes.
Pain reduction in mice occurs at doses consistent with those adopted in clinical trials. The present findings confirm the relevance of selective targeting of peripheral Nav1.8 channels to
pain therapy. In light of the excellent tolerability of
dexpramipexole in humans, our results support its translational potential for treatment of
pain.