Selective and Potent Agonists and Antagonists for Investigating the Role of Mouse Oxytocin Receptors
Selective and Potent Agonists and Antagonists for Investigating the Role of Mouse Oxytocin Receptors
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DOI：
10.1124/jpet.113.202994
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发表时间：
2013-08-01
影响因子：
3.5
通讯作者：
Chini, Bice
中科院分区：
文献类型：
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作者：
Busnelli, Marta;Bulgheroni, Elisabetta;Chini, Bice
神经肽催产素（OT）和加压素（AVP）已被证明在社会行为中发挥核心作用;因此，它们已被认为是治疗以社会互动受损为特征的神经发育和精神疾病的潜在药物。然而，尽管在OT/AVP系统中携带遗传改变的小鼠品系与基础和临床前转化神经科学具有基础和临床前相关性，但小鼠OT/AVP受体亚型的药理学特征尚未完全表征。为了填补这一空白，我们已经确定了一些OT和AVP激动剂和拮抗剂在三个小鼠OT/AVP受体在神经系统中表达如下：催产素（mOTR）和加压素V1 a（mV 1aR）和V1 b（mV 1bR）亚型。这三种受体在体外瞬时表达，用于结合和细胞内信号传导测定，然后构建mOTR结构的同源模型，以研究其分子特征与人和大鼠OTR直系同源物的比较。我们的数据表明，天然配体，OT和AVP的选择性概况，在人类，大鼠和小鼠中是保守的。此外，我们发现合成肽[Thr（4）Gly（7）] OT（TGOT）对mOTR具有显著的选择性，并且与内源性OT配体一样，激活G（q）和G（i）并募集β-抑制蛋白。最后，我们报告了三种拮抗剂，表现出显着的高亲和力和选择性的mOTR。这些高度选择性的药理学工具将有助于研究mOTR的特定生理和病理作用，以开发选择性OT为基础的疗法。
The neuropeptides oxytocin (OT) and vasopressin (AVP) have been shown to play a central role in social behaviors; as a consequence, they have been recognized as potential drugs to treat neurodevelopmental and psychiatric disorders characterized by impaired social interactions. However, despite the basic and preclinical relevance of mouse strains carrying genetic alterations in the OT/AVP systems to basic and preclinical translational neuroscience, the pharmacological profile of mouse OT/AVP receptor subtypes has not been fully characterized. To fill in this gap, we have characterized a number of OT and AVP agonists and antagonists at three murine OT/AVP receptors expressed in the nervous system as follows: the oxytocin (mOTR) and vasopressin V1a (mV1aR) and V1b (mV1bR) subtypes. These three receptors were transiently expressed in vitro for binding and intracellular signaling assays, and then a homology model of the mOTR structure was constructed to investigate how its molecular features compare with human and rat OTR orthologs. Our data indicate that the selectivity profile of the natural ligands, OT and AVP, is conserved in humans, rats, and mice. Furthermore, we found that the synthetic peptide [Thr(4)Gly(7)] OT (TGOT) is remarkably selective for the mOTR and, like the endogenous OT ligand, activates G(q) and G(i) and recruits beta-arrestins. Finally, we report three antagonists that exhibit remarkably high affinities and selectivities at mOTRs. These highly selective pharmacological tools will contribute to the investigation of the specific physiologic and pathologic roles of mOTR for the development of selective OT-based therapeutics.