Identification of optically active pyrimidine derivatives as selective 5-HT_2C modulators

A series of pyrimidine derivatives 4a–i were synthesized and evaluated for their binding affinities towards 5-HT_2C receptors. With regard to designed molecules 4a–i, the influence of the size of alkyl ether and the absolute configuration of a stereogenic center on the 5-HT_2C binding affinity and selectivity was studied. The most promising diasteromeric mixtures 4d and 4e were selected in the initial radioligand binding assay and they were further synthesized as optically active forms starting from optically active alcohols 5d and 5e, prepared by an enzymatic kinetic resolution. Pyrimidine analogue (R,R)-4e displayed an excellent 5-HT_2C binding affinity with good selectivity values against a broad range of other 5-HT receptor subtypes.