Synthesis of receptor antagonists of neuropeptide Y.

We report the synthesis of receptor antagonists of neuropeptide Y (NPY) by a strategy based on synthesis of mixtures of analogs and the subsequent isolation and identification of receptor antagonists from these mixtures. After screening a series of mixtures of NPY analogs by using an NPY antagonist assay, two potent receptor antagonists, designated PYX-1 and PYX-2, were isolated from an antagonist-containing mixture. Structural analysis revealed these analogs to be Ac-[3-(2,6-dichlorobenzyl)Tyr27, D-Thr32]NPY-(27-36) amide and Ac-[3-(2,6-dichlorobenzyl)Tyr27,36,D-Thr32]NPY-(27-36) amide, respectively. The receptor antagonists inhibited release of intracellular calcium elicited by NPY in human erythroleukemia cells and displaced 3H-labeled NPY from NPY receptors in rat brain membrane. The approach of screening and identifying useful analogs from synthetic mixtures may significantly reduce the time and resources previously required for development of receptor antagonists.