Spivak C E, Waters J A, Yadav J S, Shang W C, Hermsmeier M, Liang R F, Gund T M
Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224.
J Mol Graph. 1991 Jun;9(2):105-10, 100-1. doi: 10.1016/0263-7855(91)85006-k.
A new, semirigid, nicotinic agonist (+-)-octahydro-2-methyl-trans-5 (1H)-isoquinolone methiodide was synthesized. The disposition of this agonist's nitrogen and carbonyl group conforms well to the prevailing notion of a pharmacophore for the nicotinic receptor. Comparing its structure and electrostatic potential surfaces, we predicted that its activity would be similar to that of carbamylcholine at the frog neuromuscular junction. Instead, the potency of the isoquinolone was only 0.015 times as potent as (+)-carbamylcholine. We conclude, after eliminating other possibilities, that the vicinity of the carbonyl group of an agonist must be planar to fit a confined space within the receptor's recognition site. The isoquinolone is a weak agonist because its methylene group beta to the carbonyl intrudes on this space.
合成了一种新型半刚性烟碱激动剂（±）-八氢-2-甲基-反式-5（1H）-异喹啉甲碘化物。该激动剂的氮和羰基布局与烟碱受体药效团的主流概念非常契合。通过比较其结构和静电势表面，我们预测其活性在蛙神经肌肉接头处与氨甲酰胆碱相似。然而，异喹啉的效力仅为（+）-氨甲酰胆碱的0.015倍。在排除其他可能性后，我们得出结论，激动剂羰基附近必须是平面的，才能契合受体识别位点内的受限空间。异喹啉是一种弱激动剂，因为其羰基β位的亚甲基侵入了该空间。
