Maayani S, Weinstein H, Cohen S, Sokolovsky M
Proc Natl Acad Sci U S A. 1973 Nov;70(11):3103-7. doi: 10.1073/pnas.70.11.3103.
A study of the relation between the psychotropic activity and the antagonism to acetylcholine observed for some heterocyclic amino esters and compounds of the phencyclidine series suggests some common molecular structural requirements for their properties. Criteria obtained from quantum mechanical calculations of acetylcholine-like molecules indicate that their molecular reactivity with the cholinergic receptor site follows a certain dynamic interaction pattern. This pattern suggests a certain molecular arrangement essential for the interaction, which is based on the electronic properties of the molecules and therefore remains valid for the evaluation of compounds which lack any apparent similarity to acetylcholine. This type of molecular arrangement is shown to be shared by both activators and inhibitors of the acetylcholine receptor discussed here, thus supporting the hypothesis of their binding to a common receptor. The differences in biological activity are attributed to the effect of molecular structural factors which are not commonly included in the molecular arrangement based on the active groups of acetylcholine. The role of such factors is revealed by a study of the observed differences in the cholinergic and psychomimetic activities of related pairs of isomers and enantiomers of the molecules investigated. Structural factors which interfere with the conformational changes occurring in the receptor protein induced by an activator are characterized through differences obtained by the comparative investigation of the activities of the agonist acetate and the antagonist benzilate amino esters of quinuclidine, tropine, and pseudotropine. The same factors are shown in studies of the phencyclidine series to contribute to the antagonism to acetylcholine activity that is closely related to the psychomimetic activity of these drugs in the central nervous system. Similarly, phencyclidine derivatives in which the characteristic acetylcholine-like molecular arrangement is modified by various substitutions are shown to loose both anticholinergic and psychotropic behavior. This close correlation is supported by the identification of molecular regions which will generate the proper molecular arrangement in local anesthetics and morphine, compounds which are known to be involved in cholinergic mechanisms.
对某些杂环氨基酯和苯环己哌啶系列化合物的精神活性与对乙酰胆碱的拮抗作用之间关系的研究表明，它们的性质存在一些共同的分子结构要求。从类乙酰胆碱分子的量子力学计算中获得的标准表明，它们与胆碱能受体位点的分子反应遵循一定的动态相互作用模式。这种模式表明了相互作用所必需的某种分子排列，它基于分子的电子性质，因此对于评估与乙酰胆碱没有任何明显相似性的化合物仍然有效。这里讨论的乙酰胆碱受体的激活剂和抑制剂都具有这种分子排列类型，从而支持了它们与共同受体结合的假说。生物活性的差异归因于分子结构因素的影响，这些因素通常不包括在基于乙酰胆碱活性基团的分子排列中。通过研究所研究分子的相关异构体和对映体对在胆碱能和拟精神活性方面观察到的差异，揭示了这些因素的作用。通过对激动剂醋酸酯和奎宁环、托品和假托品的拮抗剂苯甲酸酯氨基酯的活性进行比较研究而获得的差异，表征了干扰激活剂诱导的受体蛋白构象变化的结构因素。在苯环己哌啶系列的研究中表明，相同的因素导致对乙酰胆碱活性的拮抗作用，这与这些药物在中枢神经系统中的拟精神活性密切相关。同样，其中特征性的类乙酰胆碱分子排列因各种取代而改变的苯环己哌啶衍生物，显示出失去了抗胆碱能和精神活性行为。局部麻醉药和吗啡中已知参与胆碱能机制的化合物中能够产生适当分子排列的分子区域的鉴定，支持了这种密切相关性。
