SYNTHESIS AND QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS OF N-(1-BENZYLPIPERIDIN-4-YL)PHENYLACETAMIDES AND RELATED ANALOGS AS POTENT ANDSELECTIVE SIGMA(1) RECEPTOR LIGANDS

A series of N-(1-benzylpiperidin-4-yl)pherlylacetamide derivatives was synthesized and evaluated for affinity at or and oz receptors. Most o f these compounds showed a high affinity for sigma(1) receptors and a low to moderate affinity for sigma(2) receptors. The unsubstituted com pound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high a ffinity and selectivity for sigma(1) receptors (K-i) values of 3.90 nM for sigma(1) receptors and 240 nM for sigma(2) receptors. The influen ce of substitutions on the phenylacetamide aromatic ring on binding at both the sigma(1) and sigma(2) receptor has been examined through Han sch-type quantitative structure-activity relationship (QSAR) studies. In general, all 3-substituted compounds, except for the OH group, had a higher affinity for both sigma(1) and sigma(2) receptors when compar ed with the corresponding 2- and 4-substituted analogues. The selectiv ity for sigma(1) receptors displayed a trend of 3 > 2 approximate to 4 for Cl, Pr, F, NO2, and OMe substituted analogues. Halogen substituti on on the aromatic ring generally increased the affinity for sigma(2) receptors while maintaining a similar affinity for sigma(1) receptors. Substitution with electron-donating groups, such as OH, OMe, or NH2, resulted in weak or negligible affinity for sigma(2) receptors and a m oderate affinity for sigma(1) receptors. The 2-fluoro-substituted anal ogue, 11, exhibited the highest selectivity for sigma(1) receptors amo ng all compounds tested, with a K-i value of 3.56 nM for sigma(1) rece ptors and 667 nM for sigma(2) receptors. Compounds 1, 5, 9, 11, and 20 had no affinity for dopamine D-2 (IC50 > 10 000 nM) and D-3 (IC50 > 1 0 000 nM) receptors. The nanomolar binding affinity and high selectivi ty for sigma(1) receptors suggest that these compounds may be develope d as potential radiotracers for positron emission tomography or single photon emission computerized tomography imaging studies.