A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats
| Autor: | Torben R. Neelands, Andrew O. Stewart, Gricelda H. Simler, Chengmin Zhong, Andrew J. King, Chang Z. Zhu, George Doherty, Andrew M. Swensen, Ivan Milicic, Janel M. Boyce-Rustay, Cenchen Zhan, Patricia N. Banfor, Timothy A. Vortherms, Victoria E. Scott, Natalie Bratcher, Michael F. Jarvis, Wende Niforatos, Helmut Mack, Pramila Bhatia |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.drug_class Administration Oral Calcium channel blocker Pharmacology Biochemistry Rats Sprague-Dawley chemistry.chemical_compound Dorsal root ganglion medicine Animals Humans Channel blocker Neurotransmitter Piperidones Pain Measurement Neurons Analgesics Psychomotor function Dose-Response Relationship Drug Hemodynamics Calcium Channel Blockers Rats Electrophysiology HEK293 Cells Nociception medicine.anatomical_structure chemistry Neuropathic pain |
| Zdroj: | Biochemical Pharmacology. 83:406-418 |
| ISSN: | 0006-2952 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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