A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats.
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| 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.
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| Authors | Victoria E Scott, Timothy A Vortherms, Wende Niforatos, Andrew M Swensen, Torben Neelands, Ivan Milicic, Patricia N Banfor, Andrew King, Chengmin Zhong, Gricelda Simler, Cenchen Zhan, Natalie Bratcher, Janel M Boyce-Rustay, Chang Z Zhu, Pramila Bhatia, George Doherty, Helmut Mack, Andrew O Stewart, Michael F Jarvis |
| Journal | Biochemical pharmacology (Biochem Pharmacol) Vol. 83 Issue 3 Pg. 406-18 (Feb 01 2012) ISSN: 1873-2968 [Electronic] England |
| PMID | 22153861 (Publication Type: Comparative Study, Journal Article) |
| Copyright | Copyright © 2011 Elsevier Inc. All rights reserved. |
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