| Autor: |
Schaus JM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285., Titus RD, Foreman MM, Mason NR, Truex LL |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1990 Feb; Vol. 33 (2), pp. 600-7. |
| DOI: |
10.1021/jm00164a022 |
| Abstrakt: |
The aporphine alkaloids are a class of compounds known to possess activity at both D-1 and D-2 dopamine receptors. (R)-Apomorphine and (S)-bulbocapnine are examples of compounds which have agonist and antagonist activity, respectively, at D-1 receptors. A series of optically pure aporphines was synthesized and their activity at D-1 and D-2 dopamine receptors was studied. The (R)-aporphines uniformly had greater affinity for both D-1 and D-2 receptors than their S antipodes. Dihydroxy compound (R)-apomorphine, in accord with previous studies, was found to be a D-1 agonist. Aporphines possessing a single hydroxy group at C-11 are antagonists at the D-1 receptor. The corresponding methoxy compounds are virtually inactive at dopamine receptors. The most potent compounds, (R)-11-hydroxyaporphine (R-14) and (R)-10-bromo-11-hydroxyaporphine (R-26), are more potent than bulbocapnine as D-1 antagonists but are not as selective. A model for binding of aporphines to the D-1 receptor was formulated in which binding interactions between the receptor and the basic nitrogen and the C-11 hydroxy group of the aporphine are required for high-affinity binding to the receptor. The absolute configuration at C-6a determines the orientation of the N-6 lone pair and binding is optimal for the 6aR series. The agonist or antagonist activity of an aporphine is determined by the presence or absence, respectively, of a hydroxy group at C-10. A hydrophobic binding site may be present and may account for the high antagonist activity of (S)-bulbocapnine. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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