Neuropeptide Y Antagonists: Clinical Promise and Recent Developments

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Abstract
Neuropeptide Y (NPY) is a 36 amino acid peptide and a member of the family of "PP-fold" peptides that include peptide YY (PYY) and pancreatic polypeptide (PP). Neuropeptide Y is abundant in both the central and peripheral nervous system while PYY and PP are considered to be endocrine peptides. NPY receptors have been broadly subdivided into postsynaptic Y-1 receptors and presynaptic Y2 receptors. A YI receptor has been cloned and this receptor appears to mediate several effects of NPY including vasoconstriction and anxiolysis. The Y2 receptor inhibits the release of neurotrans-mitters in the brain by inhibiting the mobilization of intracellular calcium. Additional receptors have been proposed including a Y-3 receptor that recognizes NPY, but not PYY, and a YI variant that mediates the orexigenic effects of NPY in the hypothalamus. Receptors specifically recognizing only PYY or PP have been proposed as well. One of the great difficulties of defining receptor subtypes and studying the functional role of NPY has been the absence of specific receptor antagonists. The synthesis of peptide analogs or chimeric peptides has provided a few selective agonists, but few useful peptide antagonists are available. Recently, some progress has been made in the discovery of specific non-peptide antagonists for the YI receptor. These recent developments will be described.

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