Identification of Optically Active Pyrimidine Derivatives as Selective 5-HT2C Modulators

A series of pyrimidine derivatives 4a-i were synthesized and evaluated for their binding affinities towards 5-HT2C 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-HT2C binding affinity and sel...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2017-08, Vol.22 (9), p.1416
Main Authors: Kim, Juhyeon, Jo, Hanbyeol, Lee, Hyunseung, Choo, Hyunah, Kim, Hak, Pae, Ae, Cho, Yong, Min, Sun-Joon
Format: Article
Language:English
Subjects:
5-HT2C receptor
Absolute configuration
Affinity
Alcohol
Alcohols
Binding
binding affinity
Binding sites
Chemistry
Clinical trials
enzymatic kinetic resolution
FDA approval
Hydrocarbons
Ligands
Obesity
optically active
Pharmacokinetics
pyrimidine
Schizophrenia
Selectivity
Serotonin S2 receptors
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Summary:A series of pyrimidine derivatives 4a-i were synthesized and evaluated for their binding affinities towards 5-HT2C 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-HT2C 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-HT2C binding affinity with good selectivity values against a broad range of other 5-HT receptor subtypes.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules22091416