Abstract
Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Analgesics / chemical synthesis*
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Analgesics / pharmacokinetics
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Analgesics / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cell Line
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Cricetinae
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Cricetulus
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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacokinetics
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Furans / pharmacology
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Ganglia, Spinal / cytology
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Humans
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In Vitro Techniques
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Male
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Mice
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NAV1.8 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins / physiology
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Neurons / drug effects
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Neurons / physiology
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Pain / drug therapy
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Pain / etiology
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Patch-Clamp Techniques
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Peripheral Nervous System Diseases / drug therapy
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / antagonists & inhibitors
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Sodium Channel Blockers / chemical synthesis*
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Sodium Channel Blockers / pharmacokinetics
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Sodium Channel Blockers / pharmacology
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Sodium Channels / physiology*
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Structure-Activity Relationship
Substances
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5-(4-chlorophenyl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide
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5-(4-cyanophenyl)-N-(3-methylphenyl)furan-2-carboxamide
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Amides
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Analgesics
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Anti-Inflammatory Agents, Non-Steroidal
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Furans
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NAV1.8 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins
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Recombinant Proteins
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SCN10A protein, human
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Scn10a protein, mouse
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Scn10a protein, rat
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Sodium Channel Blockers
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Sodium Channels