Open AccessSmall‐Molecule Neuromedin U Receptor 2 Agonists Suppress Food Intake and Decrease Visceral Fat in Animal Models
Author(s) -
Sampson Catherine M.,
Kasper James M.,
Felsing Daniel E.,
Raval Sweta R.,
Ye Na,
Wang Pingyuan,
Patrikeev Igor,
Rytting Erik,
Zhou Jia,
Allen John A.,
Hommel Jonathan D.
Publication year - 2018
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.425
Subject(s) - in vivo , receptor , endocrinology , agonist , population , adipose tissue , medicine , pharmacology , neuropeptide , food intake , obesity , biology , microbiology and biotechnology , environmental health
Abstract Obesity is a growing public health concern, with 37.5% of the adult population in need of therapeutics that are more efficacious with a better side effect profile. An innovative target in this regard is neuromedin U, a neuropeptide shown to suppress food intake and attenuate weight gain in animal models. These effects of neuromedin U on feeding behavior are thought to be related to agonism at the centrally expressed neuromedin U receptor 2 ( NMUR 2). As peptides present unique challenges that limit their therapeutic potential, the discovery of small‐molecule NMUR 2 agonists is needed to validate the targets therapeutic value, but to date, none have been evaluated in any animal model of disease. We therefore assessed two small‐molecule NMUR 2 agonists for their in vitro signaling and their in vivo efficacy. The NMUR 2 agonists were synthesized and both NMUR 2 agonists, NY 0116 and NY 0128, decreased cAMP while stimulating calcium signaling in stably expressing NMUR 2 HEK 293 cells. When small‐molecule NMUR 2 agonists were tested in vivo, acute administration significantly decreased high‐fat diet consumption. Repeated administration of the compounds decreased body weight and more specifically, decreased the percentage of visceral adipose tissue ( VAT ) in obese mice. These results have confirmed small‐molecule NMUR 2 agonists are efficacious in animal models to decrease fat content, food intake, and body weight, suggesting NMUR 2 is a promising therapeutic target for metabolic disorders.