摘要
多种化合物虽对组织胺类系统没有内在活性,但仍然能够提高胺能受体配体的效力3倍或3倍以上,从而显著增加活性的持续时间,防止快速耐药反应和逆转药效衰减。增强子化合物包括抗坏血酸、乙二胺四乙酸、皮质类固醇、阿片样肽、阿片类和阿片类拮抗剂。这篇文章首次对组织胺类增强剂进行了综述,这表明所有的增强剂都有一个共同的,不明显的分子基序,并通过一个共同的作用机制起效,这已由三个共同的特点得到证实。第一,胺能增强剂直接结合到它们将增强的胺,表明共同的结构基序是反映在共同的结合目标。第二,其中一个共同的目标是胺能受体的第一个细胞外环。第三,至少一些增强剂是抗磷酸二酯酶。这些观察结果表明胺能促进剂作用于胺能受体的细胞外表面,以保持受体的高亲和力状态,诱捕受体内部的配体。增强子结合产生受体结构的异构修饰干扰受体磷酸化,从而抑制受体的下调。机制解释了增强子如何增强肽能活性,提高活性的持续时间和使其他可能成为胺能增强子的化合物具有试验可预测性。
关键词: 醛固酮,异构的,变构效应,抗磷酸二酯酶,抗坏血酸,皮质类固醇,多巴胺,向下调节,EDTA,增强,提高,肾上腺素,GPCR,组胺,提高效能,分子互补,吗啡,纳洛酮,环丙甲羟二羟吗啡酮,去甲肾上腺素,镇静剂,阿片样物质,磷酸二酯酶抑制剂,加强,增强作用,血清素,过敏性,维生素C
Current Medicinal Chemistry
Title:A Common Molecular Motif Characterizes Extracellular Allosteric Enhancers of GPCR Aminergic Receptors and Suggests Enhancer Mechanism of Action
Volume: 21 Issue: 32
Author(s): Robert Root-Bernstein and Patrick F. Dillon
Affiliation:
关键词: 醛固酮,异构的,变构效应,抗磷酸二酯酶,抗坏血酸,皮质类固醇,多巴胺,向下调节,EDTA,增强,提高,肾上腺素,GPCR,组胺,提高效能,分子互补,吗啡,纳洛酮,环丙甲羟二羟吗啡酮,去甲肾上腺素,镇静剂,阿片样物质,磷酸二酯酶抑制剂,加强,增强作用,血清素,过敏性,维生素C
摘要: Several classes of compounds that have no intrinsic activity on aminergic systems nonetheless enhance the potency of aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventing tachyphylaxis and reversing fade. Enhancer compounds include ascorbic acid, ethylenediaminetetraacetic acid, corticosteroids, opioid peptides, opiates and opiate antagonists. This paper provides the first review of aminergic enhancement, demonstrating that all enhancers have a common, inobvious molecular motif and work through a common mechanism that is manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggesting that the common structural motif is reflected in common binding targets. Second, one common target is the first extracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observations suggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinity state, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptor structure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. The mechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictions about additional compounds that should act as aminergic enhancers.
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Cite this article as:
Root-Bernstein Robert and Dillon F. Patrick, A Common Molecular Motif Characterizes Extracellular Allosteric Enhancers of GPCR Aminergic Receptors and Suggests Enhancer Mechanism of Action, Current Medicinal Chemistry 2014; 21 (32) . https://dx.doi.org/10.2174/0929867321666140826120604
DOI https://dx.doi.org/10.2174/0929867321666140826120604 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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