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Discovery of a small molecule RXFP3/4 agonist that increases food intake in rats upon acute central administration.

Abstract：

:The relaxin family peptide receptors have been implicated in numerous physiological processes including energy homeostasis, cardiac function, wound healing, and reproductive function. Two family members, RXFP3 and RXFP4, are class A GPCRs with endogenous peptide ligands (relaxin-3 and insulin-like peptide 5 (INSL5), respectively). Polymorphisms in relaxin-3 and RXFP3 have been associated with obesity, diabetes, and hypercholesterolemia. Moreover, central administration of relaxin-3 in rats has been shown to increase food intake, leading to body weight gain. Reported RXFP3 and RXFP4 ligands have been restricted to peptides (both endogenous and synthetic) as well as a low molecular weight positive allosteric modulator requiring a non-endogenous orthosteric ligand. Described here is the discovery of the first potent low molecular weight dual agonists of RXFP3/4. The scaffold identified is competitive with a chimeric relaxin-3/INSL5 peptide for RXFP3 binding, elicits similar downstream signaling as relaxin-3, and increases food intake in rats following acute central administration. This is the first report of small molecule RXFP3/4 agonism.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

DeChristopher B,Park SH,Vong L,Bamford D,Cho HH,Duvadie R,Fedolak A,Hogan C,Honda T,Pandey P,Rozhitskaya O,Su L,Tomlinson E,Wallace I

doi

10.1016/j.bmcl.2019.02.013

subject

Has Abstract

pub_date

2019-04-15 00:00:00

pages

991-994

issue

8

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(19)30086-1

journal_volume

29

pub_type

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