RELATIONS BETWEEN STRUCTURE AND NICOTINE-LIKE ACTIVITY - X-RAY CRYSTAL-STRUCTURE ANALYSIS OF (-)-CYTISINE AND (-)-LOBELINE HYDROCHLORIDE AND A COMPARISON WITH (-)-NICOTINE AND OTHER NICOTINE-LIKE COMPOUNDS
RELATIONS BETWEEN STRUCTURE AND NICOTINE-LIKE ACTIVITY - X-RAY CRYSTAL-STRUCTURE ANALYSIS OF (-)-CYTISINE AND (-)-LOBELINE HYDROCHLORIDE AND A COMPARISON WITH (-)-NICOTINE AND OTHER NICOTINE-LIKE COMPOUNDS
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DOI：
10.1111/j.1476-5381.1989.tb14608.x
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发表时间：
1989-11-01
影响因子：
7.3
通讯作者：
JOHNSON, O
中科院分区：
文献类型：
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作者：
BARLOW, RB;JOHNSON, O
[1]虽然（-）-野靛碱是一种刚性结构，但它在晶体中以两种不同但非常相似的构象存在，其中吡啶酮环相对于带电氮原子的倾斜角度与（-）-碘化氢尼古丁中吡啶环的倾斜角度大致相同。然而，（-）-野靛碱的吡啶酮环中的羰基位于（-）-尼古丁中吡啶氮相对的环侧。2（-）-洛贝林HCl在25 ℃时的pKa C为8.6（约），表明（-）-洛贝林在生理pH（7.6）下至少90%为质子化形式。与受体相互作用的可能是（-）-洛贝林的苯基2-酮基-乙基部分，而不是苯基2-羟基-乙基部分。3位于平面外且有一定距离（4.5-6.5埃）的带电（“鎓”）氮原子在一个分子内的结合。许多具有烟碱样活性的化合物（例如尼古丁、野靛碱、胆碱苯基醚溴化物、二甲基苯基哌嗪鎓（DMPP）碘化物、棒炔碘化物和间羟苯基丙基三甲基碘化铵）都是如此。在一些分子中，芳环可以被不饱和基团取代，如羰基（如乙酰胆碱）或双键（如类毒素）。[4]对烟碱受体的活性似乎涉及带正电荷的氮原子和带负电荷的基团之间的相互作用，该基团可能靠近受体中的半胱氨酸残基192和193。有人建议，而不是特定的基团在分子中也参与，活性在烟碱受体依赖于一个平面部分的药物含有双键或双键系统之间的相互作用，和平面区域的受体，可能是酪氨酸或苯丙氨酸残基。
1 Although (-)-cytisine is a rigid structure, it occurs in the crystal in two distinct but very similar conformations in which the pyridone ring is tilted relative to the charged nitrogen atom at much the same angle as the pyridine ring is in (-)-nicotine hydrogen iodide. The carbonyl group in the pyridone ring of (-)-cytisine, however, is on the side of the ring opposite to the pyridine nitrogen in (-)-nicotine. 2 The pKa of (-)-lobeline HCl at 25.degree. C is 8.6 (approx), indicating that (-)-lobeline is at least 90% in the protonated form at physiological pH (7.6). It is probably the phenyl 2-keto-ethyl part of (-)-lobeline, rather than the phenyl 2-hydroxy-ethyl part, which interacts with the receptor. 3 The combination within one molecule of a charged (''onium'') nitrogen atom lying out of the plane of, and some distance (4.5-6.5 .ANG.) from an aromatic ring is common to many compounds with nicotine-like activity (e.g. nicotine, cytisine, choline phenyl ether bromide, dimethyl-phenyl-piperazinium (DMPP) iodide, coryneine iodide and m-hydroxyphenylpropyl trimethyl ammonium iodide). In some molecules the aromatic ring can be replaced by an unsaturated group, such as carbonyl (e.g. acetylcholine) or double-bonds (e.g. anatoxin). 4 Activity at nicotinic receptors appears to involve interactions between the positively charged nitrogen atom and a negatively charged group, probably close to cysteine residues 192 and 193 in the receptor. It is suggested that rather than specific groups in the molecule also being involved, activity at nicotinic receptors depends on interactions between a flat part of the drug containing double-bonds or systems of double bonds, and a planar area in the receptor, possibly tyrosine or phenylalanine residues.