title: A-887826 is a structurally novel, potent and voltage-dependent Na(v)1.8 sodium channel blocker that attenuates neuropathic tactile allodynia in rats.
abstract: 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.
authors.affiliation: Neuroscience Research, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064, USA.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Zhang
authors.forename: Char-Chang
authors.initials: CC
authors.lastname: Shieh
authors.forename: Mark L
authors.initials: ML
authors.lastname: Chapman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Matulenko
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Hakeem
authors.forename: Robert N
authors.initials: RN
authors.lastname: Atkinson
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Brian E
authors.initials: BE
authors.lastname: Marron
authors.forename: Shailen
authors.initials: S
authors.lastname: Joshi
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Krafte
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
mesh_terms: D000818:Animals; D001703:Biophysics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009437:Neuralgia / Q000150:complications / Q000209:etiology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017288:Pain Threshold / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: C552730:5-(4-butoxy-3-chlorophenyl)-N-((2-morpholinopyridin-3-yl)methyl)nicotinamide; D009025:Morpholines; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D009536:Niacinamide; D013779:Tetrodotoxin