Mistry J S, Abraham D J, Hanin I
J Med Chem. 1986 Mar;29(3):376-80. doi: 10.1021/jm00153a012.
A chronic deficiency in central cholinergic function has been implicated in a number of neuropsychiatric diseases including Alzheimer's disease. Until recently, animal models that simulate the neurochemical conditions that appear to cause these diseases in humans, as a result of a direct manipulation of the central cholinergic system, were not available. Over the past few years, however, we have been successful in developing a cholinotoxin, 1-ethyl-1-(2-hydroxyethyl)aziridinium chloride (AF64A), which has the potential to serve as a novel compound in developing animal models of human brain disorders in which a cholinergic hypofunction has been implicated. In this paper are described the design, synthesis, and testing of several structural analogues of AF64A as potential cholinotoxins, by evaluating them for their ability to inhibit high-affinity choline transport and their affinity toward brain muscarinic receptors. One of the compounds, 1-cyclopropyl-1-(2-hydroxyethyl)aziridinium chloride (i.e. aziridine analogue of 13) was found to have a remarkably high affinity (about 40 times higher than AF64A) toward brain muscarinic receptors.
中枢胆碱能功能的慢性缺陷与包括阿尔茨海默病在内的多种神经精神疾病有关。直到最近，由于直接操纵中枢胆碱能系统而模拟人类中似乎导致这些疾病的神经化学状况的动物模型还不存在。然而，在过去几年中，我们成功开发了一种胆碱毒素，即1-乙基-1-(2-羟乙基)氯化氮丙啶(AF64A)，它有潜力作为一种新型化合物用于开发涉及胆碱能功能减退的人类脑部疾病的动物模型。本文描述了AF64A的几种结构类似物作为潜在胆碱毒素的设计、合成和测试，通过评估它们抑制高亲和力胆碱转运的能力以及它们对脑毒蕈碱受体的亲和力。其中一种化合物，即1-环丙基-1-(2-羟乙基)氯化氮丙啶(即13的氮丙啶类似物)，被发现对脑毒蕈碱受体具有非常高的亲和力(比AF64A高约40倍)。
