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首页> 外文期刊>Journal of Medicinal Chemistry >Design and Characterization of Superpotent Bivalent Ligands Targeting Oxytocin Receptor Dimers via a Channel-Like Structure
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Design and Characterization of Superpotent Bivalent Ligands Targeting Oxytocin Receptor Dimers via a Channel-Like Structure

机译：通过通道样结构靶向催产素受体二聚体的超强二价配体的设计和表征

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摘要

Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogues with a well-defined spacer length (similar to 25 angstrom) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers.
机译：G蛋白偶联受体的二聚体/寡聚体状态很难确定。我们在这里报告了由两个相同的催产素模拟物组成的二价配体，它们在体外诱导催产素受体（OTRs）的G蛋白信号传导增强了3个数量级，而在体内的社交行为中，体内效价提高了100和40倍。老鼠和斑马鱼。通过受体诱变和模拟跨膜螺旋（TMH）的合成肽的干扰实验，我们表明这种超能行为源自于基于TMH1-TMH2接口的二价配体与二聚体受体的结合。此外，在这种布置中，只有具有明确定义的间隔区长度（类似于25埃）的类似物才能精确地装配在二聚体的两个前质子之间的通道状通道内。新发现的催产素二价配体代表了针对神经发育和精神疾病中二聚体OTR的强大工具，并且通常为解开G蛋白偶联受体二聚体的特定排列提供了框架。

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