Abstract
The dimeric peptide 1 (BVD-74D, as a diastereomeric mixture) is a potent and selective neuropeptide Y Y4 receptor agonist. It represents a valuable candidate in developing traceable ligands for pharmacological studies of Y4 receptors and as a lead compound for antiobesity drugs. Its optically pure stereoisomers along with analogues and fluorescently labeled variants were prepared by exploiting alkene metathesis reactions. The (2R,7R)-diaminosuberoyl containing peptide, (R,R)-1, had markedly higher affinity and agonist efficacy than its (S,S)-counterpart. Furthermore, the sulfo-Cy5 labeled (R,R)-14 retained high agonist potency as a novel fluorescent ligand for imaging Y4 receptors.
Highlights
The physiological functions of three polypeptides that form the NPY peptide family, neuropeptide Y (NPY)[1] and peptide YY (PYY),[2] and pancreatic polypeptide (PP),[3] are mediated by Y receptors, where four subtypes have been identified in human: Y1R, Y2R, Y4R and Y5R
The main challenge in developing a convenient and robust strategy for synthesising optically pure dimeric 1 analogues was to identify an optimal condition for metathesis reactions
The first approach involved pre-synthesis of the 2,7diaminosuberic acid unit bis-coupling to the linear peptidyl-resin, while the second involved a solid phase cross-metathesis between two completed linear N-terminal allylglycine containing peptides
Summary
The physiological functions of three polypeptides that form the NPY peptide family, neuropeptide Y (NPY)[1] and peptide YY (PYY),[2] and pancreatic polypeptide (PP),[3] are mediated by Y receptors, where four subtypes have been identified in human: Y1R, Y2R, Y4R and Y5R. All subtypes belong to the rhodopsin-like Gi coupled G-protein coupled receptor (GPCR) superfamily.[4] These Y receptor subtypes exhibit different binding affinity to the three members of NPY peptide family. It was found that Y1R and Y2R exhibit similar affinity to NPY and PYY, but poor affinity to PP. Y4R is a PP-selective subtype with lower affinity for NPY and PYY. All three peptides are potent at Y5R.5
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