Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1

Fazel Shabanpoor; Mohammad Akhter Hossain; Philip J Ryan; Alessia Belgi; Sharon Layfield; Martina Kocan; Suode Zhang; Chrishan S Samuel; Andrew L Gundlach; Ross A D Bathgate; Frances Separovic; John D Wade

doi:10.1021/jm201505p

Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1

J Med Chem. 2012 Feb 23;55(4):1671-81. doi: 10.1021/jm201505p. Epub 2012 Feb 8.

Authors

Fazel Shabanpoor¹, Mohammad Akhter Hossain, Philip J Ryan, Alessia Belgi, Sharon Layfield, Martina Kocan, Suode Zhang, Chrishan S Samuel, Andrew L Gundlach, Ross A D Bathgate, Frances Separovic, John D Wade

Affiliation

¹ Florey Neuroscience Institutes, The University of Melbourne, Victoria 3010, Australia.

PMID: 22257012
DOI: 10.1021/jm201505p

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Binding, Competitive
CHO Cells
Collagen / metabolism
Cricetinae
Cricetulus
Cyclic AMP / metabolism
Eating / drug effects
Fibroblasts / drug effects
Fibroblasts / metabolism
HEK293 Cells
Humans
Injections, Intraventricular
Intercellular Signaling Peptides and Proteins
Male
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Models, Molecular
Molecular Sequence Data
Peptides / pharmacology*
Phosphorylation
Protein Structure, Secondary
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Receptors, Peptide / agonists*
Receptors, Peptide / antagonists & inhibitors*
Relaxin / chemistry*
Relaxin / pharmacology
Skin / cytology
Structure-Activity Relationship

Substances

Intercellular Signaling Peptides and Proteins
Peptides
RLN3 protein, human
RXFP1 protein, human
RXFP3 protein, human
RXFP3-a2 peptide
Receptors, G-Protein-Coupled
Receptors, Peptide
Relaxin
Collagen
Cyclic AMP
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3