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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 (σ 1 R) ligands. Phenyl or pyrazolyl groups were the best in terms of affinity for the σ 1 R and the 4-(1-methylpyrazol-5-yl) derivative, 12f , was the most selective. Compound 12f is also one of the best σ 1 R 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 σ 1 R in view of its potent antinociceptive profile in several pain models in mice.