Synthesis and applications of an aldehyde-containing analogue of SCH-23390.
SCH-23390 is a high-affinity antagonist selective for D1 dopamine receptors (Ki = 2.5 nM). It does not contain a functional group that can be conveniently coupled to commercially available resins for affinity chromatography or to prepare photolabels for photoaffinity labeling of receptors. To construct an affinity resin for purification of dopamine D1 receptors, an aldehyde analogue of SCH-23390, (+/-)-7-chloro-8-hydroxy-1-(4'-formylphenyl)-3-methyl-2,3,4,5-tetrahydro -1H- 3-benzazepine (ASCH), was synthesized. 8-Methoxy-1-(4'-bromophenyl)-SCH-23390 was lithiated, formylated, and O-demethylated to form the aldehyde. NMR and IR analyses were performed to characterize the product. Assays were performed with the radioligand [125I]SCH-23982 to define the biological activity of the aldehyde. ASCH displaced [125I]SCH-23982 binding from caudate membranes with a Ki value of 7.1 nM. ASCH has been coupled through the aldehyde group on the phenyl ring to diaminodipropylamine-agarose for affinity chromatography. After solubilization of caudate membranes in 1% digitonin, the affinity resin retained binding sites for [125I]SCH-23982 that were eluted with 10 mM SCH-23390. The aldehyde was also covalently coupled to biotin hydrazide for fluorescence labeling of dopamine D1 receptors. The biotin-conjugated aldehyde of SCH-23390 displaced [125I]SCH-23982 binding from caudate membranes with a Ki value of 9.3 nM.
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Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104.
Chumpradit
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Kung
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Molinoff
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D000818:Animals; D001552:Benzazepines / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D001710:Biotin; D002421:Caudate Nucleus / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002846:Chromatography, Affinity; D003342:Corpus Striatum / Q000378:metabolism; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D011817:Rabbits; D011954:Receptors, Dopamine / Q000302:isolation & purification*; D017447:Receptors, Dopamine D1; D012116:Resins, Plant; D013055:Spectrophotometry, Infrared
C049558:8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol; D001552:Benzazepines; D007202:Indicators and Reagents; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D012116:Resins, Plant; C069576:7-chloro-8-hydroxy-1-(4'-formylphenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; D001710:Biotin