A-887826 is a structurally novel, potent and voltage-dependent Nav1.8 sodium channel blocker that attenuates neuropathic tactile allodynia in rats

Activation of sodium channels is essential to action potential generation and propagation. Recent genetic and pharmacological evidence indicates that activation of Nav1.8 channels contributes to chronic pain. Herein, we describe the identification of a novel series of structurally related pyridine derivatives as potent Nav1.8 channel blockers. A-887826 exemplifies this series and potently (IC50=11nM) blocked recombinant human Nav1.8 channels. A-887826 was ∼3 fold less potent to block Nav1.2, ∼10 fold less potent to block tetrodotoxin-sensitive sodium (TTX-S Na+) currents and was >30 fold less potent to block NaV1.5 channels. A-887826 potently blocked tetrodotoxin-resistant sodium (TTX-R Na+) currents (IC50=8nM) from small diameter rat dorsal root ganglion (DRG) neurons in a voltage-dependent fashion. A-887826 effectively suppressed evoked action potential firing when DRG neurons were held at depolarized potentials and reversibly suppressed spontaneous firing in small diameter DRG neurons from complete Freund’s adjuvant inflamed rats. Following oral administration, A-887826 significantly attenuated tactile allodynia in a rat neuropathic pain model. Further characterization of TTX-R current block in rat DRG neurons demonstrated that A-887826 (100nM) shifted the mid-point of voltage-dependent inactivation of TTX-R currents by ∼4mV without affecting voltage-dependent activation and did not exhibit frequency-dependent inhibition. The present data demonstrate that A-887826 is a structurally novel and potent Nav1.8 blocker that inhibits rat DRG TTX-R currents in a voltage-, but not frequency-dependent fashion. The ability of this structurally novel Nav1.8 blocker to effectively reduce tactile allodynia in neuropathic rats further supports the role of Nav1.8 sodium channels in pathological pain states.