The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the treatment of neuropathic pain.