Synthesis, receptor binding and functional studies of mesoridazine stereoisomers.
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).
Choi
Sungwoon
S
Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, Brigham & Women's Hospital, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Haggart
Deborah
D
Toll
Lawrence
L
Cuny
Gregory D
GD
D006801:Humans; D008653:Mesoridazine / Q000138:chemical synthesis* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013237:Stereoisomerism
D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D008653:Mesoridazine