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首页> 外文期刊>Life sciences >ASP147 in the third transmembrane helix of the rat mu opioid receptor forms ion-pairing with morphine and naltrexone.
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ASP147 in the third transmembrane helix of the rat mu opioid receptor forms ion-pairing with morphine and naltrexone.

机译：大鼠μ阿片受体的第三个跨膜螺旋中的ASP147与吗啡和纳曲酮形成离子配对。

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摘要

We tested the hypotheses that the carboxylate side chain of Asp147 of the mu opioid receptor interacts with the protonated nitrogen of naltrexone and morphine and that this interaction is important for pharmacological properties of the two compounds. Mutation of Asp147 to Ala or Asn substantially reduced the affinity of naltrexone and the affinity, potency and efficacy of morphine, while the Glu mutant had similar properties as the wildtype, indicating the significant role of the carboxylate group of Asp147 in receptor binding and activation. This role could be due to its direct interaction with ligands or involvement in interhelical interactions. The unprotonated analogs of naltrexone and morphine, cyclopropylcarbonyl noroxymorphone (CPCNOM) and N-formylnormorphine (NFNM), respectively, were used to discriminate between these mechanisms. CPCNOM was much less potent as an antagonist and had substantially lower affinity for the mu receptor than naltrexone. Similarly, NFNM was unable to activate the mu receptor and had much lower affinity than morphine. These results indicate the importance of the protonated nitrogen. Notably, the D147A and D147N mutations did not appreciably affect the binding affinities of CPCNOM and NFNM. In addition, the D147E mutant had similar affinities for CPCNOM and NFNM as the D147A and D147N mu receptors. Thus, the carboxylate group of Asp147 is not important for binding of the two unprotonated compounds. These results indicate that the carboxylate group of Asp147 of the mu receptor interacts directly with the protonated nitrogen of naltrexone and morphine and this interaction is important for binding and receptor activation.
机译：我们测试了μ阿片受体的Asp147的羧酸盐侧链与纳曲酮和吗啡的质子化氮相互作用的假设，并且这种相互作用对于这两种化合物的药理特性很重要。将Asp147突变为Ala或Asn会大大降低纳曲酮的亲和力以及吗啡的亲和力，效力和功效，而Glu突变体具有与野生型相似的特性，表明Asp147的羧酸酯基在受体结合和激活中起着重要作用。该作用可能是由于其与配体的直接相互作用或参与螺旋间的相互作用。分别使用纳曲酮和吗啡的未质子化类似物，环丙基羰基去氧吗啡酮（CPCNOM）和N-甲酰基去甲吗啡（NFNM）来区分这些机制。 CPCNOM作为拮抗剂的效力远不如纳曲酮，并且对mu受体的亲和力低得多。同样，NFNM无法激活mu受体，并且亲和力比吗啡低得多。这些结果表明质子化氮的重要性。值得注意的是，D147A和D147N突变不会明显影响CPCNOM和NFNM的结合亲和力。此外，D147E突变体对CPCNOM和NFNM具有与D147A和D147N mu受体相似的亲和力。因此，Asp147的羧酸根对于两个未质子化的化合物的结合并不重要。这些结果表明，mu受体的Asp147的羧酸根直接与纳曲酮和吗啡的质子化氮相互作用，这种相互作用对于结合和受体激活很重要。

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