Functional and pharmacological characterization of the first specific agonist and antagonist for the V1B receptor in mammals
Functional and pharmacological characterization of the first specific agonist and antagonist for the V1B receptor in mammals
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DOI：
10.1080/1025389032000114524
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发表时间：
2003-09-01
影响因子：
2.3
通讯作者：
Gilles, G
中科院分区：
文献类型：
--
作者：
Claudine, SLG;Sylvain, D;Gilles, G
抗利尿激素（VP）通过激活三种不同的抗利尿激素受体异构体V1a-R、V1b-R （V3-R）和V2-R，在哺乳动物中介导多种生物效应，并可能参与多种病理状态。到目前为止，仅成功设计了特异性的V1a和V2受体激动剂和拮抗剂。由于缺乏选择性的V1b-R配体和口服活性分子，V1b-R的作用仍然部分未知，这是研究与该受体相关的中枢和外周功能或病理疾病的关键工具。在这篇综述中，我们报道了前两种特异性V1b-R配体的生物学和药理学特性：d[Cha(4)] AVP，一种高亲和力的V1b-R激动剂和SSR149415，一种有效的口服活性V1b-R拮抗剂，对其他VP/OT受体亚型具有良好的选择性，能够在体外和体内控制ACTH分泌。事实上，这些分子为探索VP通过V1b受体介导的中枢和外周作用提供了宝贵的工具。有趣的是，SSR149415显示出有效的抗焦虑和抗抑郁活性，这表明这类新药在治疗压力相关疾病、焦虑和抑郁方面具有很好的治疗潜力。
By activating three distinct vasopressin receptor isoforms called V1a-R, V1b-R (V3-R) and V2-R, vasopressin (VP) mediates a wide number of biological effects in mammals and may be involved in several pathological states. Up to now only specific V1a and V2 receptor agonists and antagonists have been successfully designed. The role of the V1b-R still remains partially unknown, due to the lack of selective V1b-R ligands and orally-active molecules, which are crucial tools for investigating the central and peripheral functions or pathological disorders associated with this receptor. In this review, we report the biological and pharmacological properties of the first two specific V1b-R ligands: d[Cha(4)] AVP, a high affinity V1b-R agonist and SSR149415, a potent orally-active V1b-R antagonist with good selectivity with respect to other VP/OT receptor isoforms and able to control ACTH secretion in vitro and in vivo. Indeed, these molecules constitute invaluable tools for exploring the central and peripheral roles of VP mediated via V1b receptors. Interestingly, SSR149415 displays potent anxiolytic and antidepressant-like activities, indicating that this new class of drugs has a promising therapeutical potential in the treatment of stress-related disorders, anxiety and depression.