Synthesis, receptor binding and functional studies of mesoridazine stereoisomers

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The four stereoisomers of mesoridazine were synthesized and evaluated in D 2, 5-HT 1A, 5-HT 2A, 5-HT 2C, D 1, and D 3 receptor binding and functional assays. Two isomers demonstrated potent D 2 receptor binding ( K i < 3 nM) and functional antagonism (IC 50 ⩽ 10 nM) activities. These two isomers also showed moderate affinity for the 5-HT 2A and D 3 receptors. A third isomer was devoid of significant D 2 receptor binding, but did have moderate affinity for the 5-HT 2A and D 3 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).