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Identification and pharmacological properties of E339–3D6, the first nonpeptidic apelin receptor agonist
Author(s) -
Iturrioz Xavier,
AlvearPerez Rodrigo,
De Mota Nadia,
Franchet Christel,
Guillier Fabrice,
Leroux Vincent,
Dabire Hubert,
Le Jouan Melissande,
Chabane Hadjila,
Gerbier Romain,
Bonnet Dominique,
Berdeaux Alain,
Maigret Bernard,
Galzi JeanLuc,
Hibert Marcel,
LlorensCortes Catherine
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-140715
Subject(s) - apelin , agonist , receptor , chemistry , internalization , partial agonist , g protein coupled receptor , vasodilation , pharmacology , endocrinology , medicine , biology , biochemistry
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, X., Alvear‐Perez, R., De Mota, N., Franchet, C., Guillier, F., Leroux, V., Dabire, H., Le Jouan, M., Chabane, H., Gerbier, R., Bonnet, D., Berdeaux, A., Maigret, B., Galzi J.‐L., Hibert, M., Llorens‐Cortes, C. Identification and pharmacological properties of E339–3D6, FASEB J. 24, 1506–1517 (2010). www.fasebj.org