A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats.

By London Spine

A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats.

Biochem Pharmacol. 2012 Feb 1;83(3):406-18

Authors: Scott VE, Vortherms TA, Niforatos W, Swensen AM, Neelands T, Milicic I, Banfor PN, King A, Zhong C, Simler G, Zhan C, Bratcher N, Boyce-Rustay JM, Zhu CZ, Bhatia P, Doherty G, Mack H, Stewart AO, Jarvis MF

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 (IC??=0.8 ?M and 1.4 ?M, respectively) and T-type (IC??=4.6 ?M and 1.2 ?M, respectively) Ca²? channels in FLIPR based Ca²? flux assays. A-686085 also potently blocked L-type Ca²? channels (EC??=0.6 ?M), however, A-1048400 was much less active in blocking this channel (EC??=28 ?M). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC??=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 (IC??=3.0 ?M and 1.6 ?M, 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.

PMID: 22153861 [PubMed – indexed for MEDLINE]