Resolved monophenolic 2-aminotetralins and 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines: structural and stereochemical considerations for centrally acting pre- and postsynaptic dopamine-receptor agonists.
Resolved monophenolic 2-aminotetralins and 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines: structural and stereochemical considerations for centrally acting pre- and postsynaptic dopamine-receptor agonists.
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解析单酚2-氨基四氢化萘和1,2,3,4,4a,5,6,10b-八氢苯并[f]喹啉：中枢作用的突触前和突触后多巴胺受体激动剂的结构和立体化学考虑因素。
DOI：
10.1021/jm00380a012
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发表时间：
1985
影响因子：
7.3
通讯作者：
A. Carlsson
中科院分区：
文献类型：
--
作者：
H. Wikström;B. Andersson;D. Sanchez;P. Lindberg;L. Arvidsson;A. Johansson;J. Nilsson;K. Svensson;S. Hjorth;A. Carlsson
一个详细的结构-活性关系，揭示了解决，中枢作用多巴胺（DA）激动剂作用于突触前和突触后DA受体。拆分的化合物为5-和7-羟基-2-（二正丙基氨基）四氢萘以及顺式和反式-7-羟基-4-正丙基-1，2，3，4，4a，5，6，10 b-八氢苯并[f]喹啉。这些化合物的活性更强的对映异构体的结构与已知的多巴胺能激动剂，阿扑吗啡和麦角碱的结构相叠加，提出了一个新的DA-受体模型作为当前DA-受体理论的产物。这种受体模型的最重要的概念之一是它强调多巴胺能化合物的N-取代基可能采取的立场。这些位置中的一个在空间上被很好地限定，而另一个方向在空间上不那么关键。该模型已被用来解释缺乏多巴胺能活性的一些以前报道的结构，也预测新的结构，包括固有的手性，这应该是积极的DA受体的属性。希望这种启发式DA受体模型将导致发现更具选择性和有效的药理学工具，这最终可能导致开发用于治疗中枢神经系统中多巴胺能功能疾病的治疗剂。
A detailed structure-activity relationship is revealed for resolved, centrally acting dopamine (DA) agonists acting on both pre- and postsynaptic DA receptors. The compounds resolved are 5- and 7-hydroxy-2-(di-n-propylamino)tetralin and cis- and trans-7-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinoline. By the superimposition of the structures of the more active enantiomers of these compounds with those of known dopaminergic agonists, apomorphine and ergolines, a new DA-receptor model is proposed as an outgrowth of current DA-receptor theories. One of the most important concepts of this receptor model is its emphasis on the possible positions taken by the N-substituents of dopaminergic compounds. One of these positions i sterically well defined while the other direction is sterically less critical. The model has been used to explain the lack of dopaminergic activity of some previously reported structures and also to predict properties of novel structures, including inherent chirality, which should be active at DA receptors. Hopefully, this heuristic DA-receptor model will lead to the discovery of more selective and potent pharmacological tools, which ultimately might lead to the development of therapeutic agents for treating diseases of dopaminergic function in the central nervous system.