Abstract
The development of new therapies for chronic pain is an area of unmet medical need. Central to pathways of chronic pain is the upregulation of voltage-gated sodium channels. The use of tricyclic antidepressants, which also have sodium channel activity, in chronic pain therapy prompted us to develop novel compounds from this scaffold. Herein, we show that the tricyclic moiety is not needed for effective inhibition of the [(3)H]-BTX binding site and sodium currents of hNa(v)1.2. Our lead compound 6, containing a diphenyl amine motif, demonstrated a 53% inhibitory block of Na(v)1.2 currents at 10microM, which is greater than 50% increase in current block in comparison to the amitriptyline standard. Altogether our study establishes that the tricyclic motif is unnecessary for hNa(v)1.2 activity and modification of the amine portion is detrimental to sodium channel block.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amitriptyline / pharmacology
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Antidepressive Agents, Tricyclic / pharmacology
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Cells, Cultured
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Diphenylamine / chemical synthesis
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Diphenylamine / chemistry
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Diphenylamine / pharmacology*
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Electrophysiology
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Humans
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Ion Channel Gating / drug effects
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Ion Channel Gating / physiology
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Kidney / cytology
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Kidney / drug effects
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NAV1.2 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins / antagonists & inhibitors*
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Nerve Tissue Proteins / metabolism
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Patch-Clamp Techniques
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Sodium Channel Blockers / chemical synthesis
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Sodium Channel Blockers / chemistry
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Sodium Channel Blockers / pharmacology*
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Sodium Channels / metabolism
Substances
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Antidepressive Agents, Tricyclic
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NAV1.2 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins
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SCN2A protein, human
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Sodium Channel Blockers
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Sodium Channels
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Amitriptyline
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Diphenylamine