(AMINOALKOXY)CHROMONES - SELECTIVE SIGMA RECEPTOR LIGANDS

A series of (aminoalkoxy)chromones has been prepared, members of which bind potently (16-100 nM) at the sigma-binding site and bind weakly (> 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 > 5-position > 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 [H-3]DTG site, 19 nM at the [H-3]-(+)-3-PPP site, and 4000 nM (K(i)) 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 [H-3]-(+)-3-PPP site, and 21 000 nM (K(i)) 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.