SYNTHESIS AND EVALUATION OF ARYL-SUBSTITUTED (ARYLETHYL)-N-METHYL-2-(1-PYRROLIDINYL)ETHYLAMINES AND CORRESPONDING ARYLACETAMIDES FOR SIGMA-RECEPTOR AFFINITY

A series of aryl-monosubstituted arylacetamides (4-9) and arylethylene diamine (10-18) compounds were synthesized based on the structure of t he high-affinity sigma ligand N-[2-(3 ,4-dichlorophenyl)ethyl] -N-nlet hyl-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 t hat 10-18 possessed higher affinity than 4-9 for both sigma sites, esp ecially when substituted with an electron-withdrawing group. The diami ne compounds 10-18 were selective for sigma-1 binding sites, whereas t he arylacetamide compounds 4-9 generally exhibited an increased select ivity far sigma-2 sites compared to sigma-1. No clear pattern between the orientation of aromatic substituents and the sigma binding activit y was observed.