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

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.

Figure optionsDownload as PowerPoint slide