Synthesis, receptor binding and functional studies of mesoridazine stereoisomers.

Sungwoon Choi, Deborah Haggart, Lawrence Toll, Gregory D Cuny

Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, Brigham & Women's Hospital, 65 Landsdowne Street, Cambridge, MA 02139, USA.

Bioorganic & medicinal chemistry letters 2004 Sep 6

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The four stereoisomers of mesoridazine were synthesized and evaluated in D2, 5-HT1A, 5-HT2A, 5-HT2C, D1, and D3 receptor binding and functional assays. Two isomers demonstrated potent D2 receptor binding (Ki < 3 nM) and functional antagonism (IC50 < or = 10 nM) activities. These two isomers also showed moderate affinity for the 5-HT2A and D3 receptors. A third isomer was devoid of significant D2 receptor binding, but did have moderate affinity for the 5-HT2A and D3 receptors. The fourth isomer demonstrated poor affinity for all the receptors tested. Most significantly, the stereochemistry of the sulfoxide moiety played a dominant role in the observed structure-activity relationship (SAR).

Citation

Sungwoon Choi, Deborah Haggart, Lawrence Toll, Gregory D Cuny. Synthesis, receptor binding and functional studies of mesoridazine stereoisomers. Bioorganic & medicinal chemistry letters. 2004 Sep 6;14(17):4379-82