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首页> 外文期刊>Biochemistry >Different Interaction between the Agonist JN403 and the Competitive Antagonist Methyllycaconitine with the Human α7 Nicotinic Acetylcholine Receptor
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Different Interaction between the Agonist JN403 and the Competitive Antagonist Methyllycaconitine with the Human α7 Nicotinic Acetylcholine Receptor

机译：激动剂JN403和竞争性拮抗剂甲基降糖康宁与人α7烟碱乙酰胆碱受体的不同相互作用

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摘要

The interaction of the agonist JN403 with the human (h) R7 nicotinic acetylcholine receptorn(AChR) was compared to that for the competitive antagonist methyllycaconitine (MLA). The receptornselectivity of JN403 was studied on the hR7, hR3β4, and hR4β2 AChRs. The results established that thencationic center and the hydrophobic group found in JN430 and MLA are important for the interaction withnthe AChRs. MLA preincubation inhibits JN403-induced Ca2þ influx in GH3-hR7 cells with a potency 160-nfold higher than that when MLA is co-injected with JN403. The most probable explanation, based on ourndynamics results, is that MLA (more specifically the 3-methyl-2,5-dioxopyrrole ring and the B-D rings)nstabilizes the resting conformational state. The order of receptor specificity for JN403 is as follows: hR7>nhR3β4(∼40-fold) > hR4β2(∼500-fold). This specificity is based on a larger number of hydrogen bondsnbetween the carbamate group (another pharmacophore) of JN403 and the hR7 sites, the electrostaticnrepulsion between the positively charged residues around the hR3β4 sites and the cationic center of JN403,nfewer hydrogen bonds for the interaction of JN403 with the hR3β4 AChR, and an unfavorable van derWaalsninteraction between JN403 and the R4-β2 interface. The higher receptor specificity for JN403 could benimportant for the treatment of R7-related disorders, including dementias, pain-related ailments, depression,nanxiety, and wound healing.
机译：将激动剂JN403与人（h）R7烟碱乙酰胆碱受体（AChR）的相互作用与竞争性拮抗剂甲基甘可尼丁（MLA）的相互作用进行了比较。在hR7，hR3β4和hR4β2AChRs上研究了JN403的受体选择性。结果表明，JN430和MLA中的阳离子中心和疏水基团对于与AChRs的相互作用很重要。 MLA预温育可抑制JN403诱导的GH3-hR7细胞Ca2 +内流，其效力比MLA与JN403共注射时高160倍。根据我们的动力学结果，最可能的解释是MLA（更具体地说是3-甲基-2,5-二氧杂吡咯环和B-D环）稳定了静止构象状态。对JN403的受体特异性的顺序如下：hR7＞nhR3β4（〜40倍）＞hR4β2（〜500倍）。这种特异性是基于JN403的氨基甲酸酯基团（另一个药效团）与hR7位点之间的大量氢键，hR3β4位点周围带正电荷的残基与JN403的阳离子中心之间的静电排斥，从而使氢键之间的相互作用较少的氢键。具有hR3β4AChR的JN403，以及JN403与R4-β2界面之间不利的范德华相互作用。 JN403的更高的受体特异性对于治疗R7相关疾病（包括痴呆，疼痛相关疾病，抑郁症，焦虑症和伤口愈合）可能不重要。

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  • 来源
    《Biochemistry》 |2010年第19期|p.4169-4180|共12页
  • 作者

    Hugo R. Arias Ruo-Xu Gu Dominik Feuerbach and Dong-Qing Wei;

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    ‡Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, Arizona 85308,§College of LifeScience and Biotechnology, Shanghai Jiaotong University, Shanghai, China, and ) Neuroscience Research, Novartis Institutes forBiomedical Research, Basel, Switzerland ^These authors contributed equally to this work.;

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