title: A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats.
abstract: 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.
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA. Electronic address: michael.jarvis@abbvie.com.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Scott
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Chu
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Wende
authors.initials: W
authors.lastname: Niforatos
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Shailen
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D059350:Chronic Pain / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006574:Heterocyclic Compounds, 2-Ring / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D059226:Nociceptive Pain / Q000188:drug therapy* / Q000378:metabolism; D010525:Peripheral Nerves / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D006574:Heterocyclic Compounds, 2-Ring; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D013449:Sulfonamides; C000589982:4-chloro-2-fluoro-N-(2-fluorophenyl)-5-(hexahydropyrrolo(1,2-a)pyrazin-2(1H)-ylcarbonyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C121855:CACNA1G protein, human; C479952:CACNA1H protein, human; C469757:CACNA1I protein, human
keywords: Dorsal root ganglion; Neuropathic pain; Nociceptive pain; T-type Ca(2+) channels