Synthesis and evaluation of aryl-substituted N-(arylethyl)-N-methyl-2-(1-pyrrolidinyl)ethylamines and corresponding arylacetamides for sigma receptor affinity.
A series of aryl-monosubstituted arylacetamides (4-9) and arylethylenediamine (10-18) compounds were synthesized based on the structure of the high-affinity sigma ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (2). These compounds were prepared to evaluate the effect of aromatic substitution patterns on sigma-1 and sigma-2 receptor binding affinity and selectivity. The data indicate that 10-18 possessed higher affinity than 4-9 for both sigma sites, especially when substituted with an electron-withdrawing group. The diamine compounds 10-18 were selective for sigma-1 binding sites, whereas the arylacetamide compounds 4-9 generally exhibited an increased selectivity for sigma-2 sites compared to sigma-1. No clear pattern between the orientation of aromatic substituents and the sigma binding activity was observed.
Zhang
Y
Y
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, USA.
Williams
W
W
Bowen
W D
WD
Rice
K C
KC
D000081:Acetamides / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D005021:Ethylamines / Q000138:chemical synthesis* / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000081:Acetamides; D005021:Ethylamines; D017480:Receptors, sigma