Neuropeptide Y (NPY), a thirty-six amino acid peptide neurotransmitter with sequence homologies to the endocrine hormones of the pancreatic polypeptide and PYY families, is thought to fold into a compact, globular structure in solution. In earlier studies we identified benextramine (1) as an NPY receptor antagonist based on its chemical similarities to a NPY pharmacophore model. In addition, we synthesized SC3117 (2), SC3199 (3) and CC2137 (4) as NPY functional group mimetics and characterized them as mild to potent, Y(2)-selective NPY receptor antagonists in the rat femoral artery. This proposal extends on our rational design of NPY receptor non-peptide antagonists and is based on the hypothesis that benextramine is a functional group mimetic of the NPY pharmacophore. First, we propose a direct test for the NPY structural model by synthesis of conformationally restricted analogs of the peptide agonists NPY(13-36) and NPY. The conformational properties of these peptides will be assessed by circular dichroism and (1)H-NMR spectroscopy. Second, we propose SAR studies on the NPY functional group mimetics 2-4. We will test the contribution of the following chemical and structural features to Y(2)-receptor selectivity and potency: i) stereochemistry, ii) the """"""""outer"""""""" amines, iii) the basicity versus hydrogen bonding properties of the guanidines, and iv) symmetry. These third generation antagonists of the NPY receptor have been designed with regards to increasing their membrane partition properties, potency and selectivity. Third, we outline an approach to the design of Y(1)-selective peptidomimetics. These appropriately substituted benzodiazepines attempt to mimic the conformation restriction which in peptide agonists confer Y(1)-selectivity. Each of these peptide and non-peptide analogs of NPY will be tested for receptor binding potency, intrinsic activity and competitive antagonist activity in tissues with homogeneous receptor populations representative of the Y(1) and Y(2) NPY receptors and the variant types of each, and in tissues with heterogeneous NPY receptor populations that are physiologically relevant NPY's in vivo activities. These NPY receptor antagonists have relevance as tools for elucidating the in vivo role of NPY in the peripheral and central nervous systems, and as drugs (or appropriate leads for the development of drugs) for the treatment of cardiovascular disease and eating disorders, including obesity, anorexia nervosa, and bulimia.
