Neuropeptide Y(NPY), a 36-residue peptide amide isolated from porcine brain, is a member of a family of homologous hormones including peptide YY and pancreatic polypeptide. NPY is widely distributed in the central and peripheral nervous system and occurs in higher concentrations in mammalian brain and heart than any other peptide isolated to date. NPY has been implicated in a number of central and peripheral regulatory roles and is now considered as one of the most potent vasopressor and orexigenic peptides. It has also been shown to inhibit coronary flow, contractility and heart rate in isolated hearts. These observations and the findings that NPY levels are elevated in the plasma of hypertensive rats, patients with congestive heart failure (CHF) and pheochromocytoma, and in the hypothalamus of obese rats suggest that NPY sequence may be modulated for therapeutic use. Investigations have shown that nearly the entire sequence of NPY is required to elicit pressor and orexigenic responses and that these effects are mediated by the same class of receptors (Y-1). Furthermore, we have shown that NPY actions on the heart are mediated by atypical receptors and that NPY (18-36) is a competitive cardiac NPY receptor antagonist. It is therefore proposed to synthesize analogs of NPY and NPY (18-36), and investigate the receptor affinities and the effects on adenylate cyclase activity using the SK-N-MC cell line, a model system for Y-1 receptors mediating NPY effects on feeding and blood pressure, and rat cardiac ventricular membranes, respectively. These investigations are expected to result in the development of agonist and antagonist peptides with selective properties for specific targets. These analogs will have great significance both in fundamental studies as well as in the development of therapeutic drugs for a variety of conditions including feeding disorders and hypertension.
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