Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and challenges
Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and challenges
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DOI：
10.1042/bst0350737
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发表时间：
2007-08-01
影响因子：
3.9
通讯作者：
Manning, M.
中科院分区：
文献类型：
--
作者：
Chini, B.;Manning, M.
由于不同受体亚型之间的巨大相似性以及活性配体之间的高度化学相似性，作用于催产素/血管加压素受体的选择性激动剂的设计和开发一直是一个困难的任务。近几十年来，已经合成了至少一千个合成肽，并检测了它们与不同的OT/AVP受体结合和激活的能力；这一努力导致在大鼠中发现了几种受体亚型选择性激动剂。然而，由于大鼠和人AVP/OT受体之间的物种差异，这些肽在人类受体分析中表现出不同的选择性。此外，受体混杂的发现，即单一受体亚型与几种不同G蛋白偶联的能力，导致了一类全新的化合物的定义，这里称为偶联选择性配体，它可能在单一受体亚型中仅激活特定的信号通路。最后，越来越多的证据表明GPCRs(G蛋白偶联受体)不是作为单体发挥作用，而是作为二聚体/低聚物发挥作用，这开启了另一类特定配体-双价配体的设计，其中两个激动剂和/或拮抗剂部分由适当长度的间隔物连接，从而允许在二聚体内的两个亚基同时结合。这些二价配体的药理性质和选择性还有待研究，可能会导致非常新颖的研究工具和潜在的治疗剂。
The design and development of selective agonists acting at the OT (oxytocin)/AVP (vasopressin) receptors has been and continues to be a difficult task because of the great similarity among the different receptor subtypes as well as the high degree of chemical similarity between the active ligands. In recent decades, at least a thousand synthetic peptides have been synthesized and examined for their ability to bind to and activate the different OT/AVP receptors; an effort that has led to the identification of several receptor subtype-selective agonists in the rat. However, owing to species differences between rat and human AVP/OT receptors, these pepticles do not exhibit the same selectivities in human receptor assays. Furthermore, the discovery of receptor promiscuity, which is the ability of a single receptor subtype to couple to several different G-proteins, has led to the definition of a completely new class of compounds, referred to here as coupling-selective ligands, which may activate, within a single receptor subtype, only a specific signalling pathway. Finally, the accumulating evidence that GPCRs (G-protein-coupled receptors) do not function as monomers, but as dimers/oligomers, opens up the design of another class of specific ligands, bivalent ligands, in which two agonist and/or antagonist moieties are joined by a spacer of the appropriate length to allow the simultaneous binding at the two subunits within the dimer. The pharmacological properties and selectivity profiles of these bivalent ligands, which remain to be investigated, could lead to highly novel research tools and potential therapeutic agents.