Structure-Activity Relationships of Nonpeptide Neuropeptide Y Receptor Antagonists

Abstract

Reports in 1990 on some weakly to moderately active nonpeptides which were not originally designed for neuropeptide Y (NPY) receptors, followed by the discovery of the first highly potent and selective Y1 receptor antagonists-the (R)-argininamide BIBP 3226 and the benzamidine deriv. SR 120819A-as well as raising hope for novel drug treatment of hypertension, obesity and metabolic diseases stimulated the search for NPY-blocking compds. Most of the currently known nonpeptidic NPY antagonists are ligands of Y1 or Y5 receptors, whereas only one class of Y2 selective antagonists around the (S)-arginine deriv. BIIE 0246 was disclosed. Nonpeptidic ligands of the Y4 receptor are not known. In some cases the design of Y1 antagonists followed rational strategies considering amino acids which are essential for binding to Y1 and/or Y2 receptors according to results of a complete alanine scan of NPY. Typical Y1 antagonists (e.g., compds. of the argininamide, benzamidine, benzimidazole, indole and aminopyridine series) have one or 2 basic groups which-according to the working hypothesis-could mimic Arg33 and/or Arg35 in NPY. Binding models derived for some compds. (e.g., BIBP 3226 and J-104870) based on investigations with Y1 receptor mutants suggest key interactions between the basic group(s) and acidic residues of the Y1 receptor protein, esp. Asp287. Compared to Y1 antagonists the known Y5 antagonists are often based on hits from screening of libraries and show a considerably higher degree of structural diversity. Nevertheless many highly active Y5 antagonists represent a common structural pattern suggesting at least overlapping binding sites.