A-887826 is a structurally novel, potent and voltage-dependent Na(v)1.8 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 Na(v)1.8 channels contributes to chronic pain. Herein, we describe the identification of a novel series of structurally related pyridine derivatives as potent Na(v)1.8 channel blockers. A-887826 exemplifies this series and potently (IC(50)=11nM) blocked recombinant human Na(v)1.8 channels. A-887826 was approximately 3 fold less potent to block Na(v)1.2, approximately 10 fold less potent to block tetrodotoxin-sensitive sodium (TTX-S Na(+)) currents and was >30 fold less potent to block Na(V)1.5 channels. A-887826 potently blocked tetrodotoxin-resistant sodium (TTX-R Na(+)) currents (IC(50)=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 approximately 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 Na(v)1.8 blocker that inhibits rat DRG TTX-R currents in a voltage-, but not frequency-dependent fashion. The ability of this structurally novel Na(v)1.8 blocker to effectively reduce tactile allodynia in neuropathic rats further supports the role of Na(v)1.8 sodium channels in pathological pain states.

Zhang XF ，Shieh CC ，Chapman ML ，Matulenko MA ，Hakeem AH ，Atkinson RN ，Kort ME ，Marron BE ，Joshi S ，Honore P ，Faltynek CR ，Krafte DS ，Jarvis MF ... -  《-》

Functional tetrodotoxin-resistant Na(+) channels are expressed presynaptically in rat dorsal root ganglia neurons.

Medvedeva YV ，Kim MS ，Schnizler K ，Usachev YM ... -  《NEUROSCIENCE》

Analysis of the variation in use-dependent inactivation of high-threshold tetrodotoxin-resistant sodium currents recorded from rat sensory neurons.

Tripathi PK ，Trujillo L ，Cardenas CA ，Cardenas CG ，de Armendi AJ ，Scroggs RS ... -  《NEUROSCIENCE》

A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.

Jarvis MF ，Honore P ，Shieh CC ，Chapman M ，Joshi S ，Zhang XF ，Kort M ，Carroll W ，Marron B ，Atkinson R ，Thomas J ，Liu D ，Krambis M ，Liu Y ，McGaraughty S ，Chu K ，Roeloffs R ，Zhong C ，Mikusa JP ，Hernandez G ，Gauvin D ，Wade C ，Zhu C ，Pai M ，Scanio M ，Shi L ，Drizin I ，Gregg R ，Matulenko M ，Hakeem A ，Gross M ，Johnson M ，Marsh K ，Wagoner PK ，Sullivan JP ，Faltynek CR ，Krafte DS ... -  《-》

Differential action potentials and firing patterns in injured and uninjured small dorsal root ganglion neurons after nerve injury.

Zhang XF ，Zhu CZ ，Thimmapaya R ，Choi WS ，Honore P ，Scott VE ，Kroeger PE ，Sullivan JP ，Faltynek CR ，Gopalakrishnan M ，Shieh CC ... -  《BRAIN RESEARCH》