Synthesis, resolution, absolute stereochemistry, and enantioselectivity of 3',4'-dihydroxynomifensine.
3',4'-Dihydroxynomifensine, 8-amino-1,2,3,4-tetrahydro-4-(3,4-dihydroxyphenyl)-2-methylisoquinoli ne (1a), is an agonist of dopamine receptors in central and peripheral systems. Since this dopamine receptor agonist bears an asymmetric center at position 4, its synthesis and resolution were undertaken as part of a study directed toward determining the mode of interaction of these agents with the receptor(s). The enantiomers of 3',4'-dihydroxynomifensine are of particular interest, as they provide additional probes of present conceptual models of the dopamine receptor(s). Initial attempts to prepare 1a were inefficient or unsuccessful; instead, an isomeric compound, 1,2,4,5-tetra-hydro-2-(3,4-dihydroxyphenyl)-4- methyl-3H-1,4-benzodiazepine (9), was obtained. For this reason, a new route to 3',4'-dihydroxynomifensine was employed. The racemic dimethoxy intermediate 1d, thus obtained, was resolved. Methoxyl cleavage of the isomers of 1d afforded the enantiomers of 1a. Enantiomeric excess of these antipodes or appropriate derivatives was examined by NMR, CD, and HPLC methods. CD analysis suggests an enantiomeric excess greater than 99%. Determination of the absolute configuration of the enantiomers of 1a was determined by single-crystal X-ray diffractometric analysis. Examination of the isomers in several pharmacological test systems revealed a high degree of enantioselectivity. D-1 dopaminergic activity resides almost exclusively in the S enantiomer. The findings of the study have been employed to suggest an accessory binding site on the dopamine receptor(s) that differs from that advanced earlier. This accessory binding site may be specific for the D-1 subpopulation of dopamine receptors.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D002421:Caudate Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002942:Circular Dichroism; D003000:Clonidine / Q000378:metabolism; D054755:Imidazoline Receptors; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000138:chemical synthesis*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009627:Nomifensine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2; D011954:Receptors, Dopamine / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D054755:Imidazoline Receptors; D007202:Indicators and Reagents; D007546:Isoquinolines; D011942:Receptors, Adrenergic, alpha; D018341:Receptors, Adrenergic, alpha-2; D011954:Receptors, Dopamine; C031611:spiroperidol receptor; D009627:Nomifensine; D013134:Spiperone; C024878:3',4'-dihydroxynomifensine; D000262:Adenylyl Cyclases; D003000:Clonidine