Pyrazolo[3,4-d]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.
J.L. Diaz,Jordi Corbera,Daniel Martínez,Magda Bordas,Cristina Sicre,Rosalia Pascual,Mª José Pretel,Ana Paz Marín,Ana Montero,Albert Dordal,Inés Álvarez,Carmen Almansa +11 more
TL;DR: 12f was identified as an antagonist of the σ1R in view of its potent antinociceptive profile in several pain models in mice and is one of the best ρ1R ligands ever described in terms of lipophilic ligand efficiency.
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Abstract: 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.
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Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases.
TL;DR: This review provides up-to-date information on the selective targeting of σ1 receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as ρ1 selective orthosteric ligands or allosteric modulators.
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