In Stellung 4 und 2,4 substituierte 5,6-Tetramethylenpyrimidine

Buděšínský, Z.; Roubínek, F.

doi:10.1135/cccc19642341

Cited by 12 publications

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“…Column chromatography was performed on silica gel (Macherey-Nagel, Silica 60, 0.015–0.04 mm), Rf (retardation factors) and solvent systems are given for each compound. 4-Chloropyrimidines 2a [ 44 ], 2b [ 45 ], 2d [ 46 ], 2e [ 47 ], 4-fluoropyrimidine N -oxide 6 [ 43 ] and 2-methyl-3,5,6,7,8,9-hexahydro-4 H -cyclohepta[ d ]pyrimidin-4-one [ 48 ] were obtained via the described methods. All other starting materials were commercially available.…”

Section: Methodsmentioning

confidence: 99%

Novel Nanomolar Allosteric Modulators of AMPA Receptor of Bis(pyrimidine) Series: Synthesis, Biotesting and SAR Analysis

et al. 2022

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Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA receptor’s allosteric binding-site. In the present work, novel bis(pyrimidines) were studied as AMPA receptor modulators. A convenient and flexible preparative approach to bis(pyrimidines) containing a hydroquinone linker was elaborated, and a series of derivatives with varied substituents was obtained. The compounds were examined in the patch clamp experiments for their influence on the kainate-induced currents, and 10 of them were found to have potentiating properties. The best potency was found for 2-methyl-4-(4-((2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)phenoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine, which potentiated the kainate-induced currents by up to 77% in all tested concentrations (10−12–10−6 M). The results were rationalized via the modeling of modulator complexes with the dimeric ligand binding domain of the GluA2 AMPA receptor, using molecular docking and molecular dynamics simulation. The prediction of ADMET, physicochemical, and PAINS properties of the studied bis(pyrimidines) confirmed that PAMs of this type may act as the potential lead compounds for the development of neuroprotective drugs.

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