title: A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats.
abstract: Blockade of voltage-gated Ca²⁺ channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²⁺ channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC₅₀=0.8 μM and 1.4 μM, respectively) and T-type (IC₅₀=4.6 μM and 1.2 μM, respectively) Ca²⁺ channels in FLIPR based Ca²⁺ flux assays. A-686085 also potently blocked L-type Ca²⁺ channels (EC₅₀=0.6 μM), however, A-1048400 was much less active in blocking this channel (EC₅₀=28 μM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC₅₀=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²⁺ currents in rat dorsal root ganglion neurons (IC₅₀=3.0 μM and 1.6 μM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²⁺ channels coupled with pharmacological selectivity vs. L-type Ca²⁺ channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Victoria.E.Scott@Abbott.com
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Scott
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Vortherms
authors.forename: Wende
authors.initials: W
authors.lastname: Niforatos
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swensen
authors.forename: Torben
authors.initials: T
authors.lastname: Neelands
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Banfor
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Gricelda
authors.initials: G
authors.lastname: Simler
authors.forename: Cenchen
authors.initials: C
authors.lastname: Zhan
authors.forename: Natalie
authors.initials: N
authors.lastname: Bratcher
authors.forename: Janel M
authors.initials: JM
authors.lastname: Boyce-Rustay
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Pramila
authors.initials: P
authors.lastname: Bhatia
authors.forename: George
authors.initials: G
authors.lastname: Doherty
authors.forename: Helmut
authors.initials: H
authors.lastname: Mack
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010881:Piperidones / Q000008:administration & dosage* / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C569967:A-1048400; D000700:Analgesics; D002121:Calcium Channel Blockers; D010881:Piperidones