Laboratoire d'Innovation Thérapeutique, UMR7200 CNRS/Université de Strasbourg, Faculté de Pharmacie, 74 Route du Rhin, 67412 Illkirch, France.
J Med Chem. 2012 Oct 25;55(20):8588-602. doi: 10.1021/jm3006146. Epub 2012 Oct 5.
A series of fluorescent benzazepine ligands for the arginine-vasopressin V₂ receptor (AVP V₂R) was synthesized using "Click" chemistry. Their in vitro pharmacological profile at AVP V₂R, V(1a)R, V(1b)R, and oxytocin receptor was measured by binding assay and functional studies. Compound 9p, labeled with Lissamine Rhodamine B using novel solid-phase organic tagging (SPOrT) resin, exhibited a high affinity for V₂R (4.0 nM), an excellent selectivity toward V₂R and antagonist properties. By changing the nature of the dye, DY647 and Lumi4-Tb probes 44 and 47 still display a high affinity for V₂R (5.6 and 5.8 nM, respectively). These antagonists constitute the first high-affinity selective nonpeptidic fluorescent ligands for V₂R. They enabled the development of V₂R time-resolved FRET-based assay readily amenable to high-throughput screening. Taking advantage of their selectivity, these compounds were also successfully involved in the study of V(1a)R-V₂R dimerization on cell surface.
使用“点击”化学合成了一系列用于精氨酸加压素 V₂ 受体（AVP V₂R）的荧光苯并氮杂䓬配体。通过结合测定和功能研究，测量了它们在 AVP V₂R、V(1a)R、V(1b)R 和催产素受体上的体外药理学特性。用新型固相有机标记（SPOrT）树脂标记的 Lissamine Rhodamine B 的化合物 9p 对 V₂R 具有高亲和力（4.0 nM），对 V₂R 具有优异的选择性和拮抗剂特性。通过改变染料的性质，DY647 和 Lumi4-Tb 探针 44 和 47 仍然对 V₂R 具有高亲和力（分别为 5.6 和 5.8 nM）。这些拮抗剂构成了第一个高亲和力的选择性非肽荧光 V₂R 配体。它们使基于 V₂R 时间分辨荧光共振能量转移的测定法的开发变得容易适用于高通量筛选。利用它们的选择性，这些化合物还成功地参与了细胞表面上 V(1a)R-V₂R 二聚化的研究。
