Minimization of Human Relaxin-3 Leading to High-Affinity Analogues with Increased Selectivity for Relaxin-Family Peptide 3 Receptor (RXFP3) over RXFP1

被引:72
作者
Shabanpoor, Fazel [1 ,2 ]
Hossain, Mohammad Alchter [1 ,2 ]
Ryan, Philip J. [1 ,3 ]
Belgi, Alessia [1 ,4 ]
Layfield, Sharon [1 ]
Kocan, Martina [6 ]
Zhang, Suode [1 ]
Samuel, Chrishan S. [1 ,4 ]
Gundlach, Andrew L. [1 ,5 ]
Bathgate, Ross A. D. [1 ,4 ]
Separovic, Frances [2 ]
Wade, John D. [1 ,2 ]
机构
[1] Univ Melbourne, Florey Neurosci Inst, Melbourne, Vic 3010, Australia
[2] Univ Melbourne, Sch Chem, Melbourne, Vic 3010, Australia
[3] Univ Melbourne, Ctr Neurosci, Melbourne, Vic 3010, Australia
[4] Univ Melbourne, Dept Biochem & Mol Biol, Melbourne, Vic 3010, Australia
[5] Univ Melbourne, Dept Anat & Cell Biol, Melbourne, Vic 3010, Australia
[6] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic, Australia
基金
澳大利亚国家健康与医学研究理事会;
关键词
INSULIN SUPERFAMILY; CHIMERIC PEPTIDE; H3; RELAXIN; ION-PAIRS; A-CHAIN; LIGAND; INSIGHTS; GPCR142; BRAIN; LGR7;
D O I
10.1021/jm201505p
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:1671 / 1681
页数:11
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