Discovery of Small-Molecule Modulators of the Human Y4 Receptor

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.

Highly Selective Y4 Receptor Antagonist Binds in an Allosteric Binding Pocket

“…Aiming at the development of small-molecule probes to selectively target the human Y 4 R, approximately 77 000 compounds were tested by high-throughput screening (HTS). We recently reported on the discovery of Y 4 R positive allosteric modulators (PAM) from this experiment. , In comparison to PAMs and agonists, the hit rate of negative allosteric modulators (NAM) and antagonists was very low (0.022%, Table S1, Supporting Information), reflecting the challenges in the development of Y 4 R antagonists. ,, …”

“…We recently reported on the discovery of Y 4 R positive allosteric modulators (PAM) from this experiment. 12,13 In comparison to PAMs and agonists, the hit rate of negative allosteric modulators (NAM) and antagonists was very low (0.022%, Table S1, Supporting Information), reflecting the challenges in the development of Y 4 R antagonists. 11,14,15 In this study, we present the in vitro, in silico, and ex vivo characterization of the first selective, small-molecule Y 4 R allosteric antagonist (S)-VU0637120 (Figure 1a), including the identification of its binding mode that allows further preclinical studies.…”

Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators

“…Plerixafor (Mozobil, Genzyme/Sanofi) is a negative allosteric modulator at the CXCR4 receptor that promotes stem cell release for autologous transplantation [ 211 ]. Niclosamide (Bayclusid, Bayer), used as antihelmintic to treat tapeworm infestations, was found to act as a positive allosteric modulator at the neuropeptide Y4 receptor [ 212 ].…”

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

“…264 Niclosamide ( 181 ) and structurally related compounds are revealed as nonselective small molecule PAM ligands for Y 4 R versus Y 1 R, Y 2 R, and Y 5 R via HTS. 265 Further efforts yielded the small molecule tert -butylphenoxycyclohexanol (tBPC, 182 ), a purely efficacy-driven selective Y 4 R PAM, and is reported to potentiate Y 4 R activation in G-protein signaling and arrestin recruitment experiments. 266 Thus, the early efforts toward this target are promising and may yield important clinical candidates for obesity in the future.…”

“…While each member of this receptor family has been identified as a probable therapeutic target for diseases such as obesity, cancer, or other metabolic disorders, most studies have focused on the Y 4 R. Importantly, the Y 4 R has higher affinity for the endogenous ligand PP, which is secreted by pancreatic cells in proportion to caloric content intake and is thought to modulate satiety in feeding, food intake, energy homeostasis, and colon transit . Niclosamide ( 181 ) and structurally related compounds are revealed as nonselective small molecule PAM ligands for Y 4 R versus Y 1 R, Y 2 R, and Y 5 R via HTS . Further efforts yielded the small molecule tert -butylphenoxy­cyclohexanol (tBPC, 182 ), a purely efficacy-driven selective Y 4 R PAM, and is reported to potentiate Y 4 R activation in G-protein signaling and arrestin recruitment experiments .…”