4-Aminoquinolines: novel nociceptin antagonists with analgesic activity

J Med Chem. 2000 Nov 30;43(24):4667-77. doi: 10.1021/jm0002073.

Abstract

Small-molecule nociceptin antagonists were synthesized to examine their therapeutic potential. After a 4-aminoquinoline derivative was found to bind with the human ORL(1) receptor, a series of 4-aminoquinolines and related compounds were synthesized and their binding was evaluated. Elucidation of structure-activity relationships eventually led to the optimum compounds. One of these compounds, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide hydrochloride (11) not only antagonized nociceptin-induced allodynia in mice but also showed analgesic effect in a hot plate test using mice and in a formalin test using rats. Its analgesic effect was not antagonized by the opioid antagonist naloxone. These results indicate that this nociceptin antagonist has the potential to become a novel type of analgesic that differs from mu-opioid agonists.

MeSH terms

  • Adenosine Monophosphate / biosynthesis
  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology
  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Cell Line
  • Drug Evaluation, Preclinical
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Naloxone / pharmacology
  • Narcotic Antagonists / chemical synthesis*
  • Narcotic Antagonists / chemistry
  • Narcotic Antagonists / pharmacology
  • Opioid Peptides / antagonists & inhibitors*
  • Pain Measurement
  • Radioligand Assay
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship

Substances

  • Aminoquinolines
  • Analgesics
  • Benzamides
  • N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide
  • Narcotic Antagonists
  • Opioid Peptides
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Naloxone
  • Adenosine Monophosphate
  • nociceptin