title: Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist.
abstract: Apelin plays a prominent role in body fluid and cardiovascular homeostasis. To explore further upstream the role played by this peptide, nonpeptidic agonists and antagonists of the apelin receptor are required. To identify such compounds that do not exist to date, we used an original fluorescence resonance energy transfer-based assay to screen a G-protein-coupled receptor-focused library of fluorescent compounds on the human EGFP-tagged apelin receptor. This led to isolated E339-3D6 that displayed a 90 nM affinity and behaved as a partial agonist with regard to cAMP production and as a full agonist with regard to apelin receptor internalization. Finally, E339-3D6 induced vasorelaxation of rat aorta precontracted with noradrenaline and potently inhibited systemic vasopressin release in water-deprived mice when intracerebroventricularly injected. This compound represents the first nonpeptidic agonist of the apelin receptor, the optimization of which will allow development of a new generation of vasodilator and aquaretic agents.
authors.affiliation: INSERM U691, Collège de France, 11 place Marcelin Berthelot, 75005 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Iturrioz
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Alvear-Perez
authors.forename: Nadia
authors.initials: N
authors.lastname: De Mota
authors.forename: Christel
authors.initials: C
authors.lastname: Franchet
authors.forename: Fabrice
authors.initials: F
authors.lastname: Guillier
authors.forename: Vincent
authors.initials: V
authors.lastname: Leroux
authors.forename: Hubert
authors.initials: H
authors.lastname: Dabire
authors.forename: Melissande
authors.initials: M
authors.lastname: Le Jouan
authors.forename: Hadjila
authors.initials: H
authors.lastname: Chabane
authors.forename: Romain
authors.initials: R
authors.lastname: Gerbier
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.forename: Alain
authors.initials: A
authors.lastname: Berdeaux
authors.forename: Bernard
authors.initials: B
authors.lastname: Maigret
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Galzi
authors.forename: Marcel
authors.initials: M
authors.lastname: Hibert
authors.forename: Catherine
authors.initials: C
authors.lastname: Llorens-Cortes
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D000075244:Apelin Receptors; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005452:Fluoresceins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D011921:Rats, Inbred WKY; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D014664:Vasodilation; D014667:Vasopressins / Q000378:metabolism
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D004151:Dipeptides; C549403:E339-3D6 compound; D005452:Fluoresceins; D043562:Receptors, G-Protein-Coupled; D014667:Vasopressins; D005576:Colforsin; D000242:Cyclic AMP