Wikström H, Andersson B, Sanchez D, Lindberg P, Arvidsson L E, Johansson A M, Nilsson J L, Svensson K, Hjorth S, Carlsson A
J Med Chem. 1985 Feb;28(2):215-25. doi: 10.1021/jm00380a012.
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.
已揭示作用于突触前和突触后多巴胺（DA）受体的拆分型中枢作用多巴胺激动剂的详细构效关系。拆分得到的化合物为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,5,6,10b-八氢苯并[f]喹啉。通过将这些化合物活性较高的对映体结构与已知多巴胺能激动剂阿扑吗啡和麦角灵的结构进行叠加，在当前多巴胺受体理论的基础上提出了一种新的多巴胺受体模型。该受体模型最重要的概念之一是强调多巴胺能化合物N-取代基可能占据的位置。其中一个位置在空间上定义明确，而另一个方向在空间上则不那么关键。该模型已被用于解释一些先前报道结构缺乏多巴胺能活性的原因，还用于预测新结构的性质，包括应在多巴胺受体上具有活性的固有手性。有望这个启发式的多巴胺受体模型将促成发现更具选择性和效力的药理学工具，最终可能推动开发用于治疗中枢神经系统多巴胺能功能疾病的治疗药物。
