title: Mechanistic insights into the analgesic efficacy of A-1264087, a novel neuronal Ca(2+) channel blocker that reduces nociception in rat preclinical pain models.
abstract: Voltage-gated Ca(2+) channels play an important role in nociceptive transmission. There is significant evidence supporting a role for N-, T- and P/Q-type Ca(2+) channels in chronic pain. Here, we report that A-1264087, a structurally novel state-dependent blocker, inhibits each of these human Ca(2+) channels with similar potency (IC50 = 1-2 μM). A-1264087 was also shown to inhibit the release of the pronociceptive calcitonin gene-related peptide from rat dorsal root ganglion neurons. Oral administration of A-1264087 produces robust antinociceptive efficacy in monoiodoacetate-induced osteoarthritic, complete Freund adjuvant-induced inflammatory, and chronic constrictive injury of sciatic nerve-induced, neuropathic pain models with ED50 values of 3.0, 5.7, and 7.8 mg/kg (95% confidence interval = 2.2-3.5, 3.7-10, and 5.5-12.8 mg/kg), respectively. Further analysis revealed that A-1264087 also suppressed nociceptive-induced p38 and extracellular signal-regulated kinase 1/2 phosphorylation, which are biochemical markers of engagement of pain circuitry in chronic pain states. Additionally, A-1264087 inhibited both spontaneous and evoked neuronal activity in the spinal cord dorsal horn in complete Freund adjuvant-inflamed rats, providing a neurophysiological basis for the observed antihyperalgesia. A-1264087 produced no alteration of body temperature or motor coordination and no learning impairment at therapeutic plasma concentrations.
  
  
  CONCLUSIONS
  The present results demonstrate that the neuronal Ca(2+) channel blocker A-1264087 exhibits broad-spectrum efficacy through engagement of nociceptive signaling pathways in preclinical pain models in the absence of effects on psychomotor and cognitive function.
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois. Electronic address: chang.z.zhu@abbvie.com.
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Vortherms
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swensen
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Wende
authors.initials: W
authors.lastname: Niforatos
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Torben
authors.initials: T
authors.lastname: Neelands
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: La Geisha
authors.initials: LG
authors.lastname: Lewis
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Donna
authors.initials: D
authors.lastname: Gauvin
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Joseph
authors.initials: J
authors.lastname: Mikusa
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Cenchen
authors.initials: C
authors.lastname: Zhan
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Victoria
authors.initials: V
authors.lastname: Roderwald
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Chu
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Cole
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Anton
authors.initials: A
authors.lastname: Bespalov
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Xenia B
authors.initials: XB
authors.lastname: Searle
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bitner
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Bannon
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Shailen K
authors.initials: SK
authors.lastname: Joshi
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Scott
authors.affiliation: AbbVie, Research & Development, North Chicago, Chicago, Illinois.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects*; D010146:Pain / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000700:Analgesics; D053961:Azabicyclo Compounds; D002121:Calcium Channel Blockers; C000591006:N2-methyl-N-((2-(4-(trifluoromethyl)phenyl)octahydrocyclopenta(c)pyrrol-4-yl)leucinamide; D007930:Leucine
keywords: Calcium blocker; antihyperalgesia; state-dependent