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As a very abundant neuropeptide in the brain and widely distributed peptide hormone in the periphery, neuropeptide Y (NPY) appears to be a multisignaling key peptide. Together with peptide YY, pancreatic polypeptide and the four human G protein-coupled receptor subtypes hY 1 R, hY 2 R, hY 4 R and hY 5 R it forms the NPY/hYR multiligand/multireceptor system, which is involved in essential physiological processes as well as in human diseases. In particular, NPY-induced hY 1 R signaling plays a central role in the regulation of food intake and stress response as well as in obesity, mood disorders and cancer. Thus, several hY 1 R-preferring NPY analogs have been developed as versatile tools to unravel the complex NPY/hY 1 R signaling in health and disease. Further, these peptides provide basic lead structures for the development of innovative drugs. Here, the current research is summarized focusing on the development of differently sized hY 1 R-preferring NPY analogs as well as their advances with respect to hY 1 R profiling, potential therapeutic applications and targeted cancer imaging and therapy. Finally, major limitations and innovative strategies for next generation hY 1 R-preferring NPY analogs are addressed.

Chemical modification of neuropeptide Y for human Y 1 receptor targeting in health and disease