Abstract
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.
Highlights
Obesity, a major risk factor for diabetes, heart disease, cancer, and mortality is a rising medical concern with doubled worldwide prevalence since 1980, reaching an estimated medical cost of $147 billion in 2008 [1, 2]
No small molecule agonists of Y receptors have been described. Based on this lack of any structure activity data, identification of Y4 receptor (Y4R) positive allosteric modulators (PAMs) was initiated with a Ca2+-flux-based highthroughput screening (HTS) approach
Whereas VU0244224 had no effects on other Y receptor subtypes, adenosine appeared to slightly decrease signal transduction at Y1R and Y5R. These results show Niclosamide to be the most effective Y4R PAM hit compound with validated activity in a complementary assay and it alone was selected for further investigation (S1 Fig)
Summary
A major risk factor for diabetes, heart disease, cancer, and mortality is a rising medical concern with doubled worldwide prevalence since 1980, reaching an estimated medical cost of $147 billion in 2008 [1, 2]. Dietary changes and nutritional counseling can be effective treatment options but results are inconsistent, suffering from poor long-term patient adherence often leading to weight regain [3]. Only invasive treatments such as bariatric surgery show long term success rates, but are limited to patients where the benefits outweigh the risks and costs [4]. Several studies suggest that hormonal changes following bariatric surgery contribute to its long term success [2, 5]. Their respective hormone receptors may represent promising therapeutic targets. GLP-1 receptor agonists have been shown to produce weight loss and glucose homeostasis for subjects with type II diabetes. The weight loss seen with GLP-1 agonists alone is modest [6]
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