a-803467 and Peripheral-Nervous-System-Diseases

Topics: Analgesics; Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Anticonvulsants; Benzyl Compounds; Cyclopentanes; Humans; Ion Channel Gating; Pain; Peripheral Nervous System Diseases; Pyrimidines; Semicarbazones; Sodium Channel Blockers; Sodium Channels

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.

Topics: Amides; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cricetinae; Cricetulus; Furans; Ganglia, Spinal; Humans; In Vitro Techniques; Male; Mice; NAV1.8 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Neurons; Pain; Patch-Clamp Techniques; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sodium Channel Blockers; Sodium Channels; Structure-Activity Relationship