Abstract
The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.
Keywords:
ASIC-3; Pain; acid-sensing; degenerin; ion channel.
MeSH terms
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Acid Sensing Ion Channel Blockers / chemical synthesis*
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Acid Sensing Ion Channel Blockers / pharmacology*
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Acid Sensing Ion Channels / biosynthesis
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Acid Sensing Ion Channels / drug effects*
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Analgesics / chemical synthesis*
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Analgesics / pharmacology*
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Animals
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Behavior, Animal / drug effects
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Electrophysiological Phenomena
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Freund's Adjuvant
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Iodoacetates
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Isoquinolines / chemical synthesis*
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Isoquinolines / pharmacology*
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Male
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Mice
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Naphthalenes / chemical synthesis*
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Naphthalenes / pharmacology*
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Neurons / drug effects
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Neurons / metabolism
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Osteoarthritis / chemically induced
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Osteoarthritis / drug therapy
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Pain / chemically induced
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Pain / drug therapy
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Pain Measurement / drug effects
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Physical Stimulation
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Postural Balance / drug effects
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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A-317567
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ASIC1 protein, mouse
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ASIC3 protein, mouse
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Acid Sensing Ion Channel Blockers
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Acid Sensing Ion Channels
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Analgesics
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Iodoacetates
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Isoquinolines
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Naphthalenes
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Freund's Adjuvant