The replacement of acylamino by cyclic substituents in the position 4 of the pyrazolo[3,4-d]pyrimidine scaffold, led to highly active sigma-1 receptor (σ₁R) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σ₁R and the 4-(1-methylpyrazol-5-yl) derivative, 12f, was the most selective. Compound 12f is also one of the best σ₁R ligands ever described in terms of lipophilic ligand efficiency, which translates into a good physicochemical and ADMET profile. In addition, 12f was identified as an antagonist of the σ₁R in view of its potent antinociceptive profile in several pain models in mice.