Alkaloids Purified from Aristotelia chilensis Inhibit the Human α3β4 Nicotinic Acetylcholine Receptor with Higher Potencies Compared with the Human α3β4 and α7 Subtypes
Alkaloids Purified from Aristotelia chilensis Inhibit the Human α3β4 Nicotinic Acetylcholine Receptor with Higher Potencies Compared with the Human α3β4 and α7 Subtypes
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DOI：
10.1021/acs.jnatprod.9b00314
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发表时间：
2019-07-01
影响因子：
5.1
通讯作者：
Paz, Cristian
中科院分区：
文献类型：
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作者：
Arias, Hugo R.;Ortells, Marcelo O.;Paz, Cristian
从马兜铃叶中分离得到生物碱马兜铃碱(1)、马兜铃碱(2)和马兜铃酮(3)，并用核磁共振波谱对其结构进行了表征。通过钙离子内流测定，评价了这些天然化合物对人(H)α3β4、α3β4和α7烟碱型乙酰胆碱受体(AChRs)的药理活性。结果表明，这些生物碱对各受体亚型均无兴奋作用，但具有抑制作用。获得的IC50值表明了以下受体的选择性：Hα3β4>；hα4β2>；hα7。在hα3β4 AChRs的特殊情况下，1(0.40+/-0.20微米)和2(0.96+/-0.38微米)与3(167+/-3微米)相比显示出更高的势能。分子对接和结构活性关系结果表明，配体的亲脂性对于与位于-2‘和-4’位置之间的+/-离子通道胞质侧附近的管腔位置的相互作用是重要的。化合物1可作为分子支架用于开发更有效的非竞争性抑制剂，对hα3β4 AChR具有更高的选择性，可用于新的成瘾和抑郁治疗。
The alkaloids aristoteline (1), aristoquinoline (2), and aristone (3) were purified from the leaves of the Maqui tree Aristotelia chilensis and chemically characterized by NMR spectroscopy. The pharmacological activity of these natural compounds was evaluated on human (h) alpha 3 beta 4, alpha 3 beta 4, and alpha 7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results suggest that these alkaloids do not have agonistic, but inhibitory, activity on each receptor subtype. The obtained IC50 values indicate the following receptor selectivity: h alpha 3 beta 4 > h alpha 4 beta 2 >> h alpha 7. In the particular case of h alpha 3 beta 4 AChRs, 1 (0.40 +/- 0.20 mu M) and 2 (0.96 +/- 0.38 mu M) show higher potencies compared with 3 (167 +/- 3 mu M). Molecular docking and structure activity relationship results indicate that ligand lipophilicity is important for the interaction with the luminal site located close to the cytoplasmic side of the +/- ion channel between positions-2' and-4'. Compound 1 could be used as a molecular scaffold for the development of more potent noncompetitive inhibitors with higher selectivity for the h alpha 3 beta 4 AChR that could serve for novel addiction and depression therapies.