title: Structure-activity relationship of novel macrocyclic biased apelin receptor agonists.
abstract: Apelin is the endogenous ligand for the G protein-coupled receptor APJ and exerts a key role in regulating cardiovascular functions. We report herein a novel series of macrocyclic analogues of apelin-13 in which the N- and C-terminal residues as well as the macrocycle composition were chemically modified to modulate structure-activity relationships on the APJ receptor. To this end, the binding affinity and the ability to engage G protein-dependent and G protein-independent signalling pathways of the resulting analogues were assessed. In this series, the position and the nature of the C-terminal aromatic residue is a determinant for APJ interaction and β-arrestin recruitment, as previously demonstrated for linear apelin-13 derivatives. We finally discovered compounds 1, 4, 11 and 15, four potent G protein-biased apelin receptor agonists exhibiting affinity in the nanomolar range for APJ. These macrocyclic compounds represent very useful pharmacological tools to explore the therapeutic potential of the apelinergic system.
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Alexandre
authors.identifier: http://orcid.org/0000-0003-2551-9135
authors.initials: A
authors.lastname: Murza
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sainsily
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Côté
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bruneau-Cossette
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Élie
authors.identifier: http://orcid.org/0000-0002-7473-7043
authors.initials: É
authors.lastname: Besserer-Offroy
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Longpré
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca.
authors.forename: Robert
authors.initials: R
authors.lastname: Dumaine
authors.affiliation: Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lesur
authors.affiliation: Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Mannix
authors.initials: M
authors.lastname: Auger-Messier
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Sarret
authors.affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada. eric.marsault@usherbrooke.ca and Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Marsault
mesh_terms: D000818:Animals; D000075244:Apelin Receptors / Q000819:agonists*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D036341:Intercellular Signaling Peptides and Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000075244:Apelin Receptors; C491284:Aplnr protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; C495199:apelin-13 peptide