Thediscovery and synthesis of a new series of pyrimidines as potentsigma-1 receptor (σ1R) antagonists, associated withpharmacological antineuropathic pain activity, are the focus of thisarticle. The new compounds were evaluated in vitro in σ-1 andσ-2 receptor binding assays. The nature of the pyrimidine scaffoldwas crucial for activity, and a basic amine was shown to be necessaryaccording to the known pharmacophoric model. The most promising derivativewas 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine(137), which exhibited a high binding affinity to σ1R receptor (Kiσ1= 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivotests, compound 137exerted dose-dependent antinociceptiveeffects in mice formalin model and rats CCI models of neuropathicpain. In addition, no motor impairments were found in rotarod tests;acceptable pharmacokinetic properties were also noted. These datasuggest compound 137may constitute a novel class ofdrugs for the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]