The apelin receptor (APJ) is a class A G-protein-coupled receptor (GPCR) and is a putative target for the treatment of cardiovascular and metabolic diseases. Apelin-13 (NH₂-QRPRLSHKGPMPF-COOH) is a vasoactive peptide and one of the most potent endogenous inotropic agents identified to date. We report the design and discovery of a novel APJ antagonist. By using a bivalent ligand approach, we have designed compounds with two 'affinity' motifs and a short series of linker groups with different conformational and non-bonded interaction properties. One of these, cyclo(1-6)CRPRLC-KH-cyclo(9-14)CRPRLC is a competitive antagonist at APJ. Radioligand binding in CHO cells transfected with human APJ gave a K(i) value of 82 nM, competition binding in human left ventricle gave a K(D) value of 3.2 μM, and cAMP accumulation assays in CHO-K1-APJ cells gave a K(D) value of 1.32 μM.
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