Waters J A, Spivak C E, Hermsmeier M, Yadav J S, Liang R F, Gund T M
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20205.
J Med Chem. 1988 Mar;31(3):545-54. doi: 10.1021/jm00398a010.
Eight nicotinic agonists were synthesized, and their potencies were estimated by contracture of the frog rectus abdominis muscle. The most potent, 1-methyl-4-acetyl-1,2,3,6-tetrahydropyridine methiodide (3b), 50 times as potent as carbamylcholine, served as a template for the rest. Although all of the agonists could easily conform to the putative nicotinic pharmacophore, their potencies spanned a nearly 10,000-fold range. This pharmacophore, therefore, may be necessary but deficient. Computer-assisted molecular modeling studies helped to delineate additional factors that may contribute to potency. The factors are (1) the ground-state conformation, (2) superimposability of the hydrogen bond acceptor and the cationic head onto the template, (3) electrostatic potential at the cationic head and at the hydrogen bond acceptor site, and (4) the presence of a methyl group bonded to the carbon atom that bears the hydrogen bond acceptor. A new program, ARCHEM, was used to calculate and to visualize electrostatic potentials at the van der Waals surfaces of the agonists.
合成了8种烟碱激动剂，并通过蛙腹直肌挛缩来评估它们的效力。其中效力最强的1-甲基-4-乙酰基-1,2,3,6-四氢吡啶甲碘化物（3b），其效力是氨甲酰胆碱的50倍，以此作为其他激动剂的模板。尽管所有激动剂都能轻易符合假定的烟碱药效基团，但其效力范围相差近10000倍。因此，该药效基团可能是必要的，但并不充分。计算机辅助分子模拟研究有助于确定可能影响效力的其他因素。这些因素包括：（1）基态构象；（2）氢键受体和阳离子头部与模板的可叠加性；（3）阳离子头部和氢键受体位点的静电势；（4）与带有氢键受体的碳原子相连的甲基的存在。一个新程序ARCHEM被用于计算并可视化激动剂范德华表面的静电势。
