(Aminoalkoxy)chromones. Selective Sigma Receptor Ligands

J Med Chem. 1992 May 1;35(9):1526-35. doi: 10.1021/jm00087a005.

Abstract

A series of (aminoalkoxy)chromones has been prepared, members of which bind potently (16-100 nM) at the sigma binding site and bind weakly (greater than 1000 nM) at the dopamine D2 receptor and 33 other receptors, second messenger systems, and ion channels. At the sigma receptor, the preferred position of attachment for the aminoalkoxy side chain to the chromone ring followed the rank order: 7-position greater than 5-position greater than 6-position. Chromones that contained a 2-substituent that was not coplanar with the chromone ring system showed improved binding over compounds with coplanar substituents. The most potent compound at the sigma site, 7-[[7-(4-hydroxypiperidyl)heptyl]oxy]-2-phenylchromone (74), had receptor affinities (IC50) of 16 nM at the [3H]DTG site, 19 nM at the [3H]-(+)-3-PPP site, and 4000 nM (Ki) at the dopamine D2 receptor. The most selective compound examined, 6-[[6-(4-hydroxypiperidyl)hexyl]-oxy]-2-cyclopentylchromone (58), exhibited IC50s of 51 nM at the [3H]DTG site, 55 nM at the [3H]-(+)-3-PPP site, and 21,000 nM (Ki) at the dopamine D2 receptor. Compound 44 (6-[[6-(4-hydroxypiperidyl)hexyl]oxy]-3-methylflavone, NPC 16377) was systemically effective (ip and po) in two behavioral models predictive of antipsychotic compounds and systemically active in animal models of ischemia.

MeSH terms

  • Chromones / chemical synthesis
  • Chromones / metabolism*
  • Ligands
  • Receptors, Dopamine / metabolism
  • Receptors, Dopamine D2
  • Receptors, Opioid / metabolism*
  • Receptors, sigma

Substances

  • Chromones
  • Ligands
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Receptors, Opioid
  • Receptors, sigma