Selective Fluorescent Nonpeptidic Antagonists For Vasopressin V2 GPCR: Application To Ligand Screening and Oligomerization Assays.

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• 作者：St茅phanie Loison ; Martin Cottet ; H茅l猫ne Orcel ; H茅l猫ne Adihou ; Rita Rahmeh ; Laurent Lamarque ; Eric Trinquet ; Esther Kellenberger ; Marcel Hibert ; Thierry Durroux ; Bernard Mouillac ; Dominique Bonnet
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 25, 2012
• 年：2012
• 卷：55
• 期：20
• 页码：8588-8602
• 全文大小：586K
• 年卷期：v.55,no.20(October 25, 2012)
• ISSN：1520-4804

文摘

A series of fluorescent benzazepine ligands for the arginine鈥搗asopressin V₂ receptor (AVP V₂R) was synthesized using 鈥淐lick鈥?chemistry. Their in vitro pharmacological profile at AVP V₂R, V_1aR, V_1bR, 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_1aR鈥揤₂R dimerization on cell surface.