Praveen Praveen, Tailhades Julien, Rosengren K Johan, Liu Mengjie, Wade John D, Bathgate Ross A D, Hossain Mohammed Akhter
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3052, Australia.
The Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
ACS Med Chem Lett. 2020 Oct 22;11(11):2336-2340. doi: 10.1021/acsmedchemlett.0c00456. eCollection 2020 Nov 12.
The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (two disulfide bonds) suggest that the C-terminal carboxylic acid of the tryptophan residue in the B-chain is important for RXFP3 activity. In this study, we have added amide, alcohol, carbamate, and ester functionalities to the C-terminus of A2 and compared their structures and functions. As expected, the C-terminal amide form of A2 showed lower binding affinity for RXFP3 while ester and alcohol substitutions also demonstrated lower affinity. However, while these analogues showed slightly lower binding affinity, there was no significant difference in activation of RXFP3 compared to A2 bearing a C-terminal carboxylic acid, suggesting the binding pocket is able to accommodate additional atoms.
神经肽松弛素3的受体，即松弛素家族肽3（RXFP3）受体，是控制饮食、成瘾和精神行为的一个有吸引力的药理学靶点。对人松弛素3（含3个二硫键）及其类似物A2（2个二硫键）进行的多项构效关系研究表明，B链中色氨酸残基的C末端羧酸对RXFP3活性很重要。在本研究中，我们在A2的C末端添加了酰胺、醇、氨基甲酸酯和酯官能团，并比较了它们的结构和功能。正如预期的那样，A2的C末端酰胺形式对RXFP3的结合亲和力较低，而酯和醇取代物也显示出较低的亲和力。然而，虽然这些类似物的结合亲和力略低，但与带有C末端羧酸的A2相比，RXFP3的激活没有显著差异，这表明结合口袋能够容纳额外的原子。
