Aporphines as antagonists of dopamine D-1 receptors.
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.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
J M
JM
Schaus
R D
RD
Titus
M M
MM
Foreman
N R
NR
Mason
L L
LL
Truex
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001060:Aporphines / Q000494:pharmacology*; D001552:Benzazepines / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D012160:Retina; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship
D001060:Aporphines; D001552:Benzazepines; D011954:Receptors, Dopamine; D013134:Spiperone; D000262:Adenylyl Cyclases