Discovery of neuropeptide Y receptor antagonists

Publisher Summary This chapter discusses the discovery of neuropeptide Y (NPY) receptor antagonists. The design and synthesis of peptide or peptide-like NPY receptor antagonists based on the analysis of structural analogs of NPY is presented. The diphenylacetyl-dipeptide, AXC02632, was found to have high binding affinity and selectivity for the Y1 receptor. AXC02632 exhibited a much lower affinity when assayed in the presence of physiological concentrations of sodium and calcium, or when tested on intact cells. AXC02632 is structurally similar to BIBP3226 and, the latter compound is equally active in both salt-free and saline containing systems. The design and synthesis of nonpeptide NPY receptor antagonists based on pharmacophore information derived from the analysis of peptide or peptide-like NPY receptor antagonists is also analyzed. The comparison of AXC01018 with AXC01020 indicates that the desmethoxy analog AXC01020 was two times less selective for Yl over Y2 than the corresponding methoxy analog AXC01018 owing to the lack of the neutral H-bond acceptor methoxy groups. It is observed that one of the bis-triazine NPY receptor antagonists exhibited significant affinity for the rat forebrain somatistatin receptor.