Derick S, Cheng L L, Voirol M J, Stoev S, Giacomini M, Wo N C, Szeto H H, Ben Mimoun M, Andres M, Gaillard R C, Guillon G, Manning M
Institut National de la Santé et de la Recherche Médicale, Unité 469, 34094 Montpellier Cedex 05, France.
Endocrinology. 2002 Dec;143(12):4655-64. doi: 10.1210/en.2002-220363.
To date, there are no vasopressin (VP) agonists that exhibit a high affinity and selectivity for the VP V1b receptor with respect to the V1a, V2, and oxytocin receptors. In this study, we describe the synthesis and pharmacological properties of [1-deamino-4-cyclohexylalanine] arginine vasopressin (d[Cha4]AVP). Binding experiments performed on various membrane preparations revealed that d[Cha(4)]AVP exhibits a nanomolar affinity for V1b receptors from various mammalian species (rat, bovine, human). It exhibits high V1b/V1a and V1b/oxytocin selectivity for rat, human, and bovine receptors. Furthermore, it exhibits high V1b/V2 specificity for both bovine and human vasopressin receptors. Functional studies performed on biological models that naturally express V1b receptors indicate that d[Cha4]AVP is an agonist. Like VP, it stimulated basal and corticotropin-releasing factor-stimulated ACTH secretion and basal catecholamine release from rat anterior pituitary and bovine chromaffin cells, respectively. In vivo experiments performed in rat revealed that d[Cha4]AVP was able to stimulate both ACTH and corticosterone secretion and exhibits negligible vasopressor activity. It retains about 30% of the antidiuretic activity of VP. This long-sought selective VP V1b receptor ligand with nanomolar affinity will allow a better understanding of V1b-mediated VP physiological effects and is a promising new tool for V1b receptor structure-function studies.
迄今为止，尚无血管加压素（VP）激动剂对VP V1b受体相对于V1a、V2和催产素受体表现出高亲和力和选择性。在本研究中，我们描述了[1-脱氨基-4-环己基丙氨酸]精氨酸血管加压素（d[Cha4]AVP）的合成及药理特性。在各种膜制剂上进行的结合实验表明，d[Cha(4)]AVP对来自各种哺乳动物物种（大鼠、牛、人）的V1b受体表现出纳摩尔亲和力。它对大鼠、人和牛的受体表现出高V1b/V1a和V1b/催产素选择性。此外，它对牛和人的血管加压素受体均表现出高V1b/V2特异性。在天然表达V1b受体的生物学模型上进行的功能研究表明，d[Cha4]AVP是一种激动剂。与VP一样，它分别刺激大鼠垂体前叶和牛嗜铬细胞的基础促肾上腺皮质激素释放因子刺激的促肾上腺皮质激素分泌和基础儿茶酚胺释放。在大鼠中进行的体内实验表明，d[Cha4]AVP能够刺激促肾上腺皮质激素和皮质酮分泌，并且表现出可忽略不计的升压活性。它保留了约30%的VP抗利尿活性。这种长期寻求的具有纳摩尔亲和力的选择性VP V1b受体配体将有助于更好地理解V1b介导的VP生理效应，并且是用于V1b受体结构-功能研究的一种有前景的新工具。
