Neuropeptide Y receptor antagonists in obesity.
Neuropeptide Y (NPY) is a 36 amino acid amidated peptide with high sequence homology to the endocrine peptides, peptide YY (PYY) and pancreatic polypeptide (PP). They appear to interact with a family of receptors that possess high affinity for one or more of these peptides. Five members of the receptor family have been cloned, with several additional members postulated through pharmacological evidence. All are members of the seven transmembrane domain-G-protein coupled receptor family. The Y1 receptor is the best characterised, with several nonpeptide antagonists available. This receptor appears to mediate a constriction of the peripheral vasculature and the 'anxiolytic' effects of centrally administered NPY. Less is known about the other receptors in the family. The Y2 receptor is believed to be presynaptic and mediates a reduction in neurotransmitter release. The Y4 receptor appears to be the receptor for pancreatic polypeptide, with high amounts of mRNA for this receptor found in the periphery, but lower levels in the brain. The Y5 receptor is expressed in the hypothalamus and has been postulated to be the receptor which mediates the increased food consumption seen following centrally administered NPY. Finally, the Y6 receptor has been cloned in the mouse and other species, but does not appear to encode a functional gene product in humans. Several types of nonpeptide Y1 and a series of Y5 antagonists have been described in the patent literature, though these compounds have limitations that will confine their use to preclinical studies. Nevertheless, considerable progress has been made in understanding the role of NPY and its receptors in experimental obesity. The next step will be the discovery of potent and selective nonpeptide antagonists, to add further credence to the therapeutic potential.
Gehlert
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Mail Code 0510, Lilly Neuroscience, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Gehlert_Donald_R@Lilly.com
Hipskind
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