Progress in the medicinal chemistry of dopaminergic agents.

Ergot alkaloids and their derivatives have long been recognized for their potent pharmacologic activity. A number of ergot derivatives, including the dopamine agonists bromocriptine and pergolide, are currently in clinical use for the treatment of CNS and endocrine disorders. In an effort to develop more selective dopamine agonists, studies were directed to elucidate the dopaminergic pharmacophore of the ergoline nucleus. During the course of this work, it was found that the tricyclic system containing only the B-, C-, and D-rings of the ergoline skeleton (2, X = CH) possessed D-2 dopamine agonist activity. As a result of this discovery, interest was stimulated in the preparation of other heteroareno[g]quinoline systems (3, "BCD partial ergolines") for investigation of their dopaminergic properties. Factors which we found to be particularly important in determining dopaminergic activity were: (1) the nature of the heteroaromatic B ring; (2) the orientation of that heteroaromatic ring; (3) the substituents on the heteroaromatic ring; and (4) the relative and absolute stereochemistry at the CD ring fusion. We report here the synthesis and pharmacologic activity of a series of BCD partial ergolines (3) and describe how the study of these new compounds allows for the delineation of structural features important in D2 dopamine receptor activation.

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.

Resolution and absolute configuration of an ergoline-related dopamine agonist, trans-4,4a,5,6,7,8,8a,9-Octahydro-5-propyl-1H(or 2H)-pyrazolo[3,4-g]quinoline.

The title compound (+/-)-5 (R = Pro) (LY141865) has been resolved into a (-) isomer and a (+) isomer as the D- and L-tartrate salts, respectively. Biological studies have shown that dopamine agonist activity is a property of only the (-) isomer. Crystallographic analysis has proven that the absolute configuration of the active (-) isomer is the same as that of the natural ergolines.