title: Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1.
abstract: Relaxin-3 is a neuropeptide that is implicated in the regulation of stress responses and memory. The elucidation of its precise physiological role(s) has, however, been hampered by cross-activation of the relaxin-2 receptor, RXFP1, in the brain. The current study undertook to develop analogues of human relaxin-3 (H3 relaxin) that can selectively bind and activate its receptor, RXFP3. We developed a high-affinity selective agonist (analogue 2) by removal of the intra-A chain disulfide bond and deletion of 10 residues from the N terminus of the A chain. Further truncation of this analogue from the C terminus of the B chain to Cys(B22) and addition of an Arg(B23) led to a high-affinity, RXFP3-selective, competitive antagonist (analogue 3). Central administration of analogue 2 in rats increased food intake, which was blocked by prior coadministration of analogue 3. These novel RXFP3-selective peptides represent valuable pharmacological tools to study the physiological roles of H3 relaxin/RXFP3 systems in the brain and important leads for the development of novel compounds for the treatment of affective and cognitive disorders.
authors.affiliation: Florey Neuroscience Institutes, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Fazel
authors.initials: F
authors.lastname: Shabanpoor
authors.forename: Mohammad
authors.initials: M
authors.lastname: Akhter Hossain
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Ryan
authors.forename: Alessia
authors.initials: A
authors.lastname: Belgi
authors.forename: Sharon
authors.initials: S
authors.lastname: Layfield
authors.forename: Martina
authors.initials: M
authors.lastname: Kocan
authors.forename: Suode
authors.initials: S
authors.lastname: Zhang
authors.forename: Chrishan S
authors.initials: CS
authors.lastname: Samuel
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gundlach
authors.forename: Ross A D
authors.initials: RA
authors.lastname: Bathgate
authors.forename: Frances
authors.initials: F
authors.lastname: Separovic
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007276:Injections, Intraventricular; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors*; D018000:Receptors, Peptide / Q000819:agonists* / Q000037:antagonists & inhibitors*; D012065:Relaxin / Q000737:chemistry* / Q000494:pharmacology; D012867:Skin / Q000166:cytology; D013329:Structure-Activity Relationship
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C480238:RLN3 protein, human; C417543:RXFP1 protein, human; C410092:RXFP3 protein, human; C583617:RXFP3-a2 peptide; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D012065:Relaxin; D003094:Collagen; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3