Schaus J M, Kornfeld E C, Titus R D, Nichols C L, Huser D L, Clemens J A, Smalstig E B, Fuller R W
Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, IN 46285.
Drug Des Discov. 1993;9(3-4):323-32.
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.
麦角生物碱及其衍生物长期以来因其强大的药理活性而被人们所认识。包括多巴胺激动剂溴隐亭和培高利特在内的多种麦角衍生物目前正在临床中用于治疗中枢神经系统和内分泌疾病。为了开发更具选择性的多巴胺激动剂，人们开展了相关研究以阐明麦角灵核的多巴胺能药效基团。在这项工作过程中，发现仅含有麦角灵骨架的B、C和D环的三环系统（2，X = CH）具有D-2多巴胺激动剂活性。这一发现激发了人们对制备其他杂芳并[g]喹啉系统（3，“BCD部分麦角灵”）以研究其多巴胺能性质的兴趣。我们发现，在确定多巴胺能活性方面特别重要的因素包括：（1）杂芳族B环的性质；（2）该杂芳族环的取向；（3）杂芳族环上的取代基；以及（4）C-D环稠合处的相对和绝对立体化学。我们在此报告一系列BCD部分麦角灵（3）的合成及药理活性，并描述对这些新化合物的研究如何有助于描绘出在D2多巴胺受体激活中重要的结构特征。
