(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 (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 posit...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 35; no. 9; pp. 1526 - 1535
Main Authors:	Erickson, Ronald H, Natalie, Kenneth J, Bock, William, Lu, Zhijian, Farzin, Farzaneh, Sherrill, Ronald G, Meloni, David J, Patch, Raymond J, Rzesotarski, Waclaw J
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-05-1992
Subjects:	(aminoalkoxy)chromones Chemistry Chromones - chemical synthesis Chromones - metabolism Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives Ligands opioids Organic chemistry Preparations and properties receptors Receptors, Dopamine - metabolism Receptors, Dopamine D2 Receptors, Opioid - metabolism Receptors, sigma type sigma Opiate receptor D2 Dopamine receptor Bicyclic compound Aminoether Aromatic compound Selectivity Oxygen heterocycle Biological activity
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Summary:	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.
Bibliography:	ark:/67375/TPS-1RBG2R8C-Q istex:43629227F62F13C58BD95AB1C4B78A6BAA42C969 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00087a005