Food intake regulation in rodents: Y-5 or Y1NPY receptors or both?

Neuropeptide Y (NPY), one of the most abundant peptides in rat and human br ains, appears to act in the hypothalamus to stimulate feeding. It was first suggested that the NPY Y-1 receptor (Y1R) was involved in feeding stimulat ed by NPY. More recently a novel NPY receptor subtype (Y5R) was identified in rat and human as the NPY feeding receptor subtype. There is, however, no absolute consensus since selective Y1R antagonists also antagonize NPY-ind uced hyperphagia. Nevertheless, new anti-obesity drugs may emerge from furt her pharmacological characterization of the NPY receptors and their antagon ists. A large panel of Y1R and Y5R antagonists (such as CGP71683A, BIBO3304 , BIBP3226, 1229U91, and SYNAPTIC and BANYU derivatives but also patentable in-house-synthesized compounds) have been evaluated through in vitro and i n vivo tests in an attempt to establish a predictive relationship between t he binding selectivity for human receptors, the potency in isolated organs assays, and the inhibitory effect on food intake in both normal and obese h yperphagic rodents. Although these results do not allow one to conclude on the implication of a single receptor subtype at the molecular level, this a pproach is crucial for the design of novel NPY receptor antagonists with po tential use as anti-obesity drugs and for evaluation of their possible adve rse peripheral side effects, such as hypotension.