Effects of C-Terminal B-Chain Modifications in a Relaxin 3 Agonist Analogue

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Nov 20

PMID 33214850

Citations 2

Authors

Praveen Praveen

Julien Tailhades

K Johan Rosengren

Mengjie Liu

John D Wade

Ross A D Bathgate

Mohammed Akhter Hossain

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System.

Gay E, Guan D, Van Voorhies K, Vasukuttan V, Mathews K, Besheer J J Med Chem. 2022; 65(11):7959-7974.

PMID: 35594150 PMC: 9255433. DOI: 10.1021/acs.jmedchem.2c00508.

Indole-Containing Amidinohydrazones as Nonpeptide, Dual RXFP3/4 Agonists: Synthesis, Structure-Activity Relationship, and Molecular Modeling Studies.

Guan D, Rahman M, Gay E, Vasukuttan V, Mathews K, Decker A J Med Chem. 2021; 64(24):17866-17886.

PMID: 34855388 PMC: 8758203. DOI: 10.1021/acs.jmedchem.1c01081.

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