A series of N-(1-benzylpiperidin-4-yl)arylacetamides were synthesized and evaluated for their binding properties for sigma1 and sigma2 receptors. In agreement with previously reported sigma1/sigma2 receptor binding data for N-(1-benzylpiperidin-4-yl)phenylacetamide, all of the N-(1-benzylpiperidin-4-yl)arylacetamide compounds reported below displayed higher affinity for sigma1 vs sigma2 receptors. Replacement of the phenyl ring of the phenylacetamide moiety with a thiophene, naphthyl, or indole aromatic ring had no significant effect on the sigma1 receptor affinity. Replacement of the phenyl ring with an imidazole or pyridyl aromatic ring resulted in a >60-fold loss in affinity for sigma1 receptors and no significant binding affinity for sigma2 receptors. Substitution on the aromatic ring of the benzyl group showed a similar or slightly decreased affinity for sigma1 receptors. Substitution on the aromatic rings of both the phenylacetamide moiety and the benzyl group with a halogen resulted in a similar affinity for sigma(1) receptors and a significantly increased affinity for sigma2 receptors. Comparative molecular field analysis revealed that electrostatic properties of the substituents in the phenylacetamide aromatic ring strongly influenced binding to sigma1 receptors. Compounds 1, 10, 18, 22, 37, and 40 showed the highest selectivity for sigma1 receptors with K(i) (sigma2) to K(i) (sigma(1)) ratios of 100, >92, >122, 77, 74, and 80, respectively. In agreement with previously reported results, the phenylacetamide analogues had no binding affinity for dopamine receptors (D2/D3).