Minimization of Human Relaxin-3 Leading to High-Affinity Analogues with Increased Selectivity for Relaxin-Family Peptide 3 Receptor (RXFP3) over RXFP1
| Autor: | Suode Zhang, Philip Ryan, John D. Wade, Ross A. D. Bathgate, Frances Separovic, Martina Kocan, Mohammad Akhter Hossain, Andrew L. Gundlach, Sharon Layfield, Alessia Belgi, Chrishan S. Samuel, Fazel Shabanpoor |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Models Molecular Agonist Receptors Peptide medicine.drug_class Molecular Sequence Data Peptide CHO Cells Binding Competitive Protein Structure Secondary Receptors G-Protein-Coupled Rats Sprague-Dawley Eating Structure-Activity Relationship Cricetulus Cricetinae Drug Discovery Cyclic AMP medicine Animals Humans Amino Acid Sequence Phosphorylation Receptor Peptide sequence Injections Intraventricular Skin Mitogen-Activated Protein Kinase 1 chemistry.chemical_classification Relaxin Mitogen-Activated Protein Kinase 3 Fibroblasts Ligand (biochemistry) Rats HEK293 Cells chemistry Biochemistry Competitive antagonist Intercellular Signaling Peptides and Proteins Molecular Medicine Collagen Peptides Relaxin-3 hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Medicinal Chemistry. 55:1671-1681 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm201505p |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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