Neuropeptide Y Y5 receptor antagonists as anti-obesity drugs

Abstract

Neuropeptide Y (NPY) is present in the hypothalamus, where it is believed to play a key role in the control of food intake. Evidence for this assertion has come from studies demonstrating that acute administration of NPY into the hypothalamus or into the brain ventricles leads to increased food intake. In the case of chronic administration, the hyperphagic effects of NPY are prolonged, leading to the development of an obese state. NPY levels in the hypothalamus are temporally correlated with food intake and are markedly elevated in response to energy depletion. However, attempts to demonstrate an important role for NPY in the control of food intake using NPY knockout mice, NPY antisense oligodeoxynucleotides and anti-NPY antibodies has produced equivocal results. Despite this, many pharmaceutical companies have moved ahead with the search for antagonists of NPY receptor subtypes as appetite suppressant/anti-obesity agents. Antagonists of the NPY Y5 subtype seemed initially promising since analogs of NPY with high selectivity for this receptor strongly stimulated food intake. However, once again, attempts to inhibit the signaling of NPY through the NPY Y5 receptor produced equivocal effects on food intake. Many thousands of NPY Y5 antagonists have been made which fall into two main categories: those that influence food intake and those that do not. Those compounds that do inhibit food intake appear to do so by interactions with non-NPY Y5 related mechanisms. Thus, current evidence would suggest that antagonists of NPY acting through the NPY Y5 receptor subtype will not be useful appetite suppressant/anti-obesity agents.