Limited Structure-Activity Relationships for Carboxy and AminoTerminal Substitutions of Peptide YY 25–36
PYY is a naturally occurring peptide hormone of 36 amino acids in length with high homology to NPY. It is secreted from the gut (released by endocrine cells) in direct response to feeding and is active in the central nervous system. PYY binds to the Y family of GPCR receptors of which there are five sub-types (Y1-Y5). PYY participates in regulation of numerous processes including blood pressure, circadian rhythm, sexual behavior, and appetite suppression. N-terminal processing of PYY 1-36 by dipeptidyl peptidase (DPP) produces PYY 3-36, which is selective for and activates the Y2 receptor. Because PYY 3-36 is efficacious at reducing food intake in humans1 and rodents2 the appetite suppression indication is believed to be due to Y2 agonism.
Previous literature reports demonstrate that truncation of the 3–36 amide to the 13-mer acetyl PYY 24–36 amide provides a Y2R full agonist with 3–5 fold reduction in potency3. Using this as our starting point, series of discreet analogs...