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 Surendran Samuel, Andrew L Gundlach, Ross AD Bathgate, Frances Separovic, John D Wade

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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 CysB22 and addition of an ArgB23 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.
Original languageEnglish
Pages (from-to)1671 - 1681
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number4
Publication statusPublished - 2012

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