title: Discovery of a competitive apelin receptor (APJ) antagonist.
abstract: 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.
authors.affiliation: Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of Cambridge, Lensfield Road CB2 1EW, Cambridge, UK.
authors.forename: N J Maximilian
authors.initials: NJ
authors.lastname: Macaluso
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Pitkin
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Maguire
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
authors.forename: Robert C
authors.initials: RC
authors.lastname: Glen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000075244:Apelin Receptors; D001667:Binding, Competitive; D016466:CHO Cells; D002318:Cardiovascular Diseases / Q000188:drug therapy; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008659:Metabolic Diseases / Q000188:drug therapy; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D008024:Ligands; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP