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

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.
Mesh Terms:
Amino Acid Sequence, Animals, Binding, Competitive, CHO Cells, Collagen, Cricetinae, Cricetulus, Cyclic AMP, Eating, Fibroblasts, HEK293 Cells, Humans, Injections, Intraventricular, Male, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Structure, Secondary, Rats, Rats, Sprague-Dawley, Receptors, G-Protein-Coupled, Receptors, Peptide, Relaxin, Skin, Structure-Activity Relationship
J. Med. Chem.
Date: Feb. 23, 2012
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