The neuropeptide Y (NPY) system is a multireceptor/multiligand system consisting of four receptors in humans (hY1, hY2, hY4, hY5) and three agonists (NPY, PYY, PP) that activate these receptors with different potency. The relevance of this system in diseases like obesity or cancer, and the different role that each receptor plays influencing different biological processes makes this system suitable for the design of subtype selectivity studies. In this review we focus on the latest findings within the NPY system, we summarize recent mutagenesis studies, structure activity relationship studies, receptor chimera, and selective ligands focusing also on the binding mode of the native agonists.

Background:The Y 4 R is involved in regulation of food intake and gastrointestinal transport. Results: Mutagenesis studies revealed several residues displaying a significant loss of potency for hPP. Conclusion: Tops of TM2, TM6, and TM7 interact with the hY 4 R native agonist hPP. Significance: Characterizing the structure of the Y 4 R binding pocket is crucial for the development of new anti-obesity drugs.

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