Schulman J M, Sabio M L, Disch R L
J Med Chem. 1983 Jun;26(6):817-23. doi: 10.1021/jm00360a007.
A theoretical model is used to deduce the pharmacologically active conformation of acetylcholine and other agonists interacting with the muscarinic receptor of the parasympathetic and central nervous systems. This is accomplished by replacing the usual dihedral angles tau 1 and tau 2, which define the conformations of cholinergic drugs, with two new geometric parameters more suitable for describing the muscarinic pharmacophore: a characteristic distance, [PQ], and a dihedral angle, PNOQ. Values for these parameters are determined by conformational analysis on semirigid muscarinic agonists using molecular mechanics and ab initio molecular orbital methods. In addition to deducing the active conformation of acetylcholine and other agonists, the model also rationalizes the pattern of stereoselectivity in agonists related to 3-acetoxyquinuclidine (aceclidine) and furnishes a geometric criterion for partial agonism and antagonism.
一个理论模型被用于推导乙酰胆碱及其他与副交感神经系统和中枢神经系统毒蕈碱受体相互作用的激动剂的药理活性构象。这是通过用两个更适合描述毒蕈碱药效基团的新几何参数取代通常定义胆碱能药物构象的二面角τ1和τ2来实现的：一个特征距离[PQ]和一个二面角PNOQ。这些参数的值通过使用分子力学和从头算分子轨道方法对半刚性毒蕈碱激动剂进行构象分析来确定。除了推导乙酰胆碱和其他激动剂的活性构象外，该模型还解释了与3-乙酰氧基奎宁环（醋克利定）相关的激动剂中的立体选择性模式，并为部分激动和拮抗作用提供了几何标准。
