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.
The potency of beta-adrenoreceptor agonists, e.g., isoproterenol, is strikingly increased by substitution of the meta catecholic hydroxyl group with the NH group of a carbostyril system. To explore the possibility that comparable potency enhancement might occur upon similar modification of the catechol ring of dopamine, a series of 5-(2-aminoethyl)carbostyril derivatives was prepared and examined for D-1 and D-2 dopamine receptor-stimulating activity. Only the parent compound, 5-(2-aminoethyl)-8-hydroxycarbostyril (2), produced measurable activation of dopamine-sensitive adenylate cyclase (29% at a concentration of 10 microM). Some of the compounds, however, did produce significant activity in tests, namely displacement of [3H]spiroperidol binding from bovine pituitary homogenate and an isolated perfused rabbit ear artery preparation, that measure interaction with D-2 receptors. Potency of the carbostyrils was enhanced by 8-hydroxylation and by appropriate substitution of the amino group of the ethylamine side chain. The most potent member of the series was 8-hydroxy-5-[2-[[2-(4-hydroxyphenyl)ethyl]-n-propylamino]ethyl] carbostyril (16b). This compound was about 3 times more effective than dopamine in the D-2 receptor tests. Clearly, the results of this study indicate that potency of dopamine receptor agonists is not increased by carbostyril replacement of the m-hydroxyl as is noted with the beta-adrenergic receptor agonists.
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