Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist.
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.
Iturrioz
Xavier
X
INSERM U691, Collège de France, 11 place Marcelin Berthelot, 75005 Paris, France.
Alvear-Perez
Rodrigo
R
De Mota
Nadia
N
Franchet
Christel
C
Guillier
Fabrice
F
Leroux
Vincent
V
Dabire
Hubert
H
Le Jouan
Melissande
M
Chabane
Hadjila
H
Gerbier
Romain
R
Bonnet
Dominique
D
Berdeaux
Alain
A
Maigret
Bernard
B
Galzi
Jean-Luc
JL
Hibert
Marcel
M
Llorens-Cortes
Catherine
C
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
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