A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats

Biochem Pharmacol. 2014 Jun 15;89(4):536-44. doi: 10.1016/j.bcp.2014.03.015. Epub 2014 Apr 12.


Activation of T-type Ca²⁺ channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during periods of neuronal hyperexcitability. The role of T-type Ca²⁺ channels in chronic pain is supported by gene knockdown studies showing that decreased Ca(v)3.2 channel expression results in the loss of low voltage-activated (LVA) currents in dorsal root ganglion (DRG) neurons and attenuation of neuropathic pain in the chronic constriction injury (CCI) model. ABT-639 is a novel, peripherally acting, selective T-type Ca²⁺ channel blocker. ABT-639 blocks recombinant human T-type (Ca(v)3.2) Ca²⁺ channels in a voltage-dependent fashion (IC₅₀ = 2 μM) and attenuates LVA currents in rat DRG neurons (IC₅₀ = 8 μM). ABT-639 was significantly less active at other Ca²⁺ channels (e.g. Ca(v)1.2 and Ca(v)2.2) (IC₅₀ > 30 μM). ABT-639 has high oral bioavailability (%F = 73), low protein binding (88.9%) and a low brain:plasma ratio (0.05:1) in rodents. Following oral administration ABT-639 produced dose-dependent antinociception in a rat model of knee joint pain (ED₅₀ = 2 mg/kg, p.o.). ABT-639 (10-100 mg/kg, p.o.) also increased tactile allodynia thresholds in multiple models of neuropathic pain (e.g. spinal nerve ligation, CCI, and vincristine-induced). [corrected]. ABT-639 did not attenuate hyperalgesia in inflammatory pain models induced by complete Freund's adjuvant or carrageenan. At higher doses (e.g. 100-300 mg/kg) ABT-639 did not significantly alter hemodynamic or psychomotor function. The antinociceptive profile of ABT-639 provides novel insights into the role of peripheral T-type (Ca(v)3.2) channels in chronic pain states.

Keywords: Dorsal root ganglion; Neuropathic pain; Nociceptive pain; T-type Ca(2+) channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Biological Availability
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Calcium Channel Blockers / adverse effects
  • Calcium Channel Blockers / pharmacokinetics
  • Calcium Channel Blockers / pharmacology
  • Calcium Channel Blockers / therapeutic use*
  • Calcium Channels, T-Type / chemistry
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism*
  • Cells, Cultured
  • Chronic Pain / drug therapy
  • Chronic Pain / metabolism
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds, 2-Ring / adverse effects
  • Heterocyclic Compounds, 2-Ring / pharmacokinetics
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Heterocyclic Compounds, 2-Ring / therapeutic use*
  • Humans
  • Male
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Nociceptive Pain / drug therapy*
  • Nociceptive Pain / metabolism
  • Peripheral Nerves / cytology
  • Peripheral Nerves / drug effects*
  • Peripheral Nerves / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use*


  • 4-chloro-2-fluoro-N-(2-fluorophenyl)-5-(hexahydropyrrolo(1,2-a)pyrazin-2(1H)-ylcarbonyl)benzenesulfonamide
  • CACNA1G protein, human
  • CACNA1H protein, human
  • CACNA1I protein, human
  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • Heterocyclic Compounds, 2-Ring
  • Nerve Tissue Proteins
  • Recombinant Proteins
  • Sulfonamides