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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047122-02
Application #
2184532
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1993-04-01
Project End
1997-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Parker, M S; Sah, R; Park, E A et al. (2009) Oligomerization of the heptahelical G protein coupling receptors: a case for association using transmembrane helices. Mini Rev Med Chem 9:329-39
Parker, Steven L; Parker, Michael S; Wong, Ying Y et al. (2008) Importance of a N-terminal aspartate in the internalization of the neuropeptide Y Y2 receptor. Eur J Pharmacol 594:26-31
Parker, M S; Sah, R; Balasubramaniam, A et al. (2008) Dimers of the neuropeptide Y (NPY) Y2 receptor show asymmetry in agonist affinity and association with G proteins. J Recept Signal Transduct Res 28:437-51
Parker, Steven L; Parker, Michael S; Sah, Renu et al. (2008) Pertussis toxin induces parallel loss of neuropeptide Y Y1 receptor dimers and Gi alpha subunit function in CHO cells. Eur J Pharmacol 579:13-25
Parker, S L; Parker, M S; Sallee, F R et al. (2007) Oligomerization of neuropeptide Y (NPY) Y2 receptors in CHO cells depends on functional pertussis toxin-sensitive G-proteins. Regul Pept 144:72-81
Parker, S L; Parker, M S; Sah, R et al. (2007) Self-regulation of agonist activity at the Y receptors. Peptides 28:203-13
Balasubramaniam, Ambikaipakan; Mullins, Deborra E; Lin, Shu et al. (2006) Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar affinity. J Med Chem 49:2661-5
Parker, M S; Sah, R; Sheriff, S et al. (2005) Internalization of cloned pancreatic polypeptide receptors is accelerated by all types of Y4 agonists. Regul Pept 132:91-101
Shahab, M; Balasubramaniam, A; Sahu, A et al. (2003) Central nervous system receptors involved in mediating the inhibitory action of neuropeptide Y on luteinizing hormone secretion in the male rhesus monkey (Macaca mulatta). J Neuroendocrinol 15:965-70
Sheriff, Sulaiman; Chance, William T; Iqbal, Sabahat et al. (2003) Hypothalamic administration of cAMP agonist/PKA activator inhibits both schedule feeding and NPY-induced feeding in rats. Peptides 24:245-54

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