Aporphines as antagonists of dopamine D-1 receptors

• Published in: Journal of medicinal chemistry Vol. 33; no. 2; pp. 600 - 607
• Main Authors: Schaus, John M, Titus, Robert D, Foreman, Mark M, Mason, Norman R, Truex, Lewis L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-02-1990
• Subjects: Adenylyl Cyclases - metabolism; Animals; aporphines; Aporphines - pharmacology; Benzazepines - metabolism; Binding Sites; Binding, Competitive; Chemical Phenomena; Chemistry; Enzyme Activation - drug effects; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; In Vitro Techniques; Organic chemistry; Preparations and properties; Rats; Receptors, Dopamine - drug effects; Receptors, Dopamine - metabolism; Retina; Spiperone - metabolism; Structure-Activity Relationship; Alkaloid; Structure activity relation; Nitrogen heterocycle; D1 Dopamine receptor; Aromatic compound; Tetracyclic compound; Agonist antagonist; In vitro
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00164a022

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.