Discovery of Small-Molecule Modulators of the Human Y4 Receptor.
The human neuropeptide Y4 receptor (Y4R) and its native ligand, pancreatic polypeptide, are critically involved in the regulation of human metabolism by signaling satiety and regulating food intake, as well as increasing energy expenditure. Thus, this receptor represents a putative target for treatment of obesity. With respect to new approaches to treat complex metabolic disorders, especially in multi-receptor systems, small molecule allosteric modulators have been in the focus of research in the last years. However, no positive allosteric modulators or agonists of the Y4R have been described so far. In this study, small molecule compounds derived from the Niclosamide scaffold were identified by high-throughput screening to increase Y4R activity. Compounds were characterized for their potency and their effects at the human Y4R and as well as their selectivity towards Y1R, Y2R and Y5R. These compounds provide a structure-activity relationship profile around this common scaffold and lay the groundwork for hit-to-lead optimization and characterization of positive allosteric modulators of the Y4R.
Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Leipzig University, Leipzig, Germany.|Center for Structural Biology, Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
Gregory
G
Sliwoski
Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Leipzig University, Leipzig, Germany.
Mario
M
Schubert
Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Leipzig University, Leipzig, Germany.
Jan
J
Stichel
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States of America.
David
D
Weaver
Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Leipzig University, Leipzig, Germany.
Annette G
AG
Beck-Sickinger
Center for Structural Biology, Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
Jens
J
Meiler
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D009534:Niclosamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017476:Receptors, Neuropeptide Y / Q000819:agonists* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D008024:Ligands; D017476:Receptors, Neuropeptide Y; D054852:Small Molecule Libraries; C109491:neuropeptide Y4 receptor; D009534:Niclosamide