Synthesis and quantitative structure-activity relationships of N-(1-benzylpiperidin-4-yl)phenylacetamides and related analogues as potent and selective σ1 receptor ligands

A series of N-(1-benzylpiperidin-4-yl)pherlylacetamide derivatives was synthesized and evaluated for affinity at or and oz receptors. Most of these compounds showed a high affinity for sigma(1) receptors and a low to moderate affinity for sigma(2) receptors. The unsubstituted compound N-(1-benzylpiperidin-4-yl)phenylacetamide, 1, displayed a high affinity 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 influence of substitutions on the phenylacetamide aromatic ring on binding at both the sigma(1) and sigma(2) receptor has been examined through Hansch-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 compared with the corresponding 2- and 4-substituted analogues. The selectivity for sigma(1) receptors displayed a trend of 3 > 2 approximate to 4 for Cl, Pr, F, NO2, and OMe substituted analogues. Halogen substitution 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 moderate affinity for sigma(1) receptors. The 2-fluoro-substituted analogue, 11, exhibited the highest selectivity for sigma(1) receptors among all compounds tested, with a K-i value of 3.56 nM for sigma(1) receptors 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 > 10 000 nM) receptors. The nanomolar binding affinity and high selectivity for sigma(1) receptors suggest that these compounds may be developed as potential radiotracers for positron emission tomography or single photon emission computerized tomography imaging studies.