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Pyrazolo[3,4-d]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.

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

SUBMITTER: Diaz JL

PROVIDER: S-EPMC6071743 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Pyrazolo[3,4-d]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 2: Introduction of cyclic substituents in position 4.

Díaz José Luis JL Corbera Jordi J Martínez Daniel D Bordas Magda M Sicre Cristina C Pascual Rosalia R Pretel Mª José MJ Marín Ana Paz AP Montero Ana A Dordal Albert A Alvarez Inés I Almansa Carmen C

MedChemComm 20170420 6

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 go ...[more]

PMID: 30108835

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