Mager P P, Mager H, Walther H
Institute of Pharmacology and Toxicology of the University, Leipzig, Germany.
Drug Des Discov. 1993 Jun;10(2):135-56.
A profile of antimuscarinic response and its duration of action of substituted 7-amino-1-hydroxy-5-heptyn-2-ones can be correlated against the molecular space, partial energy of the nitrogen atom of the side chain, and the STERIMOL parameters maximum width and length. The molecules are conformationally rigid in the low-energy state which seems to be condition for specific interactions with accessory binding sites of the muscarinic M3 receptor. The agents can be activated energetically to more flexible compounds which may favor covalent binding to the catalytic center of the M3 receptor. On the basis of the results obtained, a common pharmacophore of three structurally diverse classes of M3 antagonists is proposed. The matrix of optimized Cartesian coordinates of a molecule can be transformed to a vector-valued observation which can be applied to develop quantitative conformation-activity relationships.
取代的7-氨基-1-羟基-5-庚炔-2-酮的抗毒蕈碱反应及其作用持续时间的概况可以与分子空间、侧链氮原子的部分能量以及STERIMOL参数最大宽度和长度相关联。这些分子在低能状态下构象刚性，这似乎是与毒蕈碱M3受体辅助结合位点发生特异性相互作用的条件。这些药物可以通过能量激活转变为更具柔性的化合物，这可能有利于与M3受体的催化中心进行共价结合。基于所获得的结果，提出了三类结构不同的M3拮抗剂的共同药效基团。分子的优化笛卡尔坐标矩阵可以转换为矢量值观测值，可用于建立定量构效关系。
