Synthesis, structure-activity relationship, and pharmacological profile of analogs of the ASIC-3 inhibitor A-317567

ACS Chem Neurosci. 2010 Jan 20;1(1):19-24. doi: 10.1021/cn9000186. Epub 2009 Oct 6.

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

  • Acid Sensing Ion Channel Blockers / chemical synthesis*
  • Acid Sensing Ion Channel Blockers / pharmacology*
  • Acid Sensing Ion Channels / biosynthesis
  • Acid Sensing Ion Channels / drug effects*
  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Electrophysiological Phenomena
  • Freund's Adjuvant
  • Iodoacetates
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / pharmacology*
  • Male
  • Mice
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / pharmacology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Osteoarthritis / chemically induced
  • Osteoarthritis / drug therapy
  • Pain / chemically induced
  • Pain / drug therapy
  • Pain Measurement / drug effects
  • Physical Stimulation
  • Postural Balance / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • A-317567
  • ASIC1 protein, mouse
  • ASIC3 protein, mouse
  • Acid Sensing Ion Channel Blockers
  • Acid Sensing Ion Channels
  • Analgesics
  • Iodoacetates
  • Isoquinolines
  • Naphthalenes
  • Freund's Adjuvant