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J Med Chem. 2012 Oct 25;55(20):8588-602. doi: 10.1021/jm3006146. Epub 2012 Oct 5.

Selective fluorescent nonpeptidic antagonists for vasopressin V₂ GPCR: application to ligand screening and oligomerization assays.

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Laboratoire d'Innovation Thérapeutique, UMR7200 CNRS/Université de Strasbourg, Faculté de Pharmacie, 74 Route du Rhin, 67412 Illkirch, France.


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.

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