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Chapter: Basic & Clinical Pharmacology : Vasoactive Peptides

Neuropeptide Y

Neuropeptide Y (NPY) is a member of the family that also includes peptide YY and pancreatic polypeptide. Each of these peptides consists of 36 amino acids.


Neuropeptide Y (NPY) is a member of the family that also includes peptide YY and pancreatic polypeptide. Each of these peptides consists of 36 amino acids.

NPY is one of the most abundant neuropeptides in both the central and peripheral nervous systems. In the sympathetic nervous

The effects of NT are mediated by three subtypes of NT recep-tors, designated NTR1, NTR2, and NTR3, also known as NTS1,NTS2, and NTS3. NTR1and NTR2receptors belong to the Gqprotein-coupled superfamily with seven transmembrane domains;

system, NPY is frequently localized in noradrenergic neurons and apparently functions both as a vasoconstrictor and as a cotransmit-ter with norepinephrine. Peptide YY and pancreatic polypeptide are both gut endocrine peptides.

NPY produces a variety of central nervous system effects, includ-ing increased feeding (it is one of the most potent orexigenic mol-ecules in the brain), hypotension, hypothermia, respiratory depression, and activation of the hypothalamic-pituitary-adrenal axis. Other effects include vasoconstriction of cerebral blood vessels, positive chronotropic and inotropic actions on the heart, and hyper-tension. The peptide is a potent renal vasoconstrictor and suppresses renin secretion, but can cause diuresis and natriuresis. Prejunctional neuronal actions include inhibition of transmitter release from sym-pathetic and parasympathetic nerves. Vascular actions include direct vasoconstriction, potentiation of the action of vasoconstrictors, and inhibition of the action of vasodilators.

These diverse effects are mediated by four subtypes of NPY receptors designated Y1, Y2, Y4, and Y5. The receptors have been cloned and shown to be Gi protein-coupled receptors linked to mobilization of Ca2+ and inhibition of adenylyl cyclase. Y1 and Y2 receptors are of major importance in the cardiovascular and other peripheral effects of the peptide. Y4 receptors have a high affinity for pancreatic polypeptide and may be a receptor for the pancreatic peptide rather than for NPY. Y5 receptors are found mainly in the central nervous system and may be involved in the control of food intake. They also mediate the activation of the hypothalamic-pituitary-adre-nal axis by NPY.

Selective nonpeptide NPY receptor antagonists are now avail-able for research. The first nonpeptide Y1 receptor antagonist, BIBP3226, is also the most thoroughly studied. It has a short half-life in vivo. In animal models, it blocks the vasoconstrictor and pressor responses to NPY. Structurally related Y1 antagonists include BIB03304 and H409/22; the latter has been tested in humans. SR120107A and SR120819A are orally active Y1 antago-nists and have a long duration of action. BIIE0246 is the first nonpeptide antagonist selective for the Y2 receptor; it does not cross the blood-brain barrier. Useful Y4 antagonists are not avail-able. The Y5 antagonists MK-0557 and S-2367 have been tested in clinical trials for obesity.

These drugs have been useful in analyzing the role of NPY in cardiovascular regulation. It now appears that the peptide is not important in the regulation of hemodynamics under normal resting conditions but may be of increased importance in cardiovascular disorders including hypertension and heart failure. Other studies haveimplicated NPY in feeding disorders, obesity, alcoholism, anxiety, depression, epilepsy, pain, cancer, and bone physiology. Y1 and par-ticularly Y5 receptor antagonists have potential as antiobesity agents.

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