Agonists for neuropeptide Y receptors Y 1 and Y 5 stimulate different phases of feeding in guinea pigs

The stimulatory effect of neuropeptide Y (NPY) on food intake is well established but the roles of the receptor subtypes Y 1 and Y 5 have been difficult to define. We have studied the effects of two novel Y 1 ‐preferring and two Y 5 ‐preferring agonists on feeding in guinea pigs. The Y 1 ‐preferring receptor agonists [Arg 6 ,Pro 34 ]pNPY and [Phe 7 ,Pro 34 ]pNPY had high affinity for the Y 1 receptor ( K i values 0.07 and 0.04 n M , respectively) and nanomolar affinity for the Y 5 receptor. Administration of either compound into the third brain ventricle increased food intake equally to NPY. The Y 5 agonist [Ala 31 ,Aib 32 ]pNPY displayed a moderate affinity for the Y 5 receptor ( K i 7.42 n M ) and a low affinity for Y 1 ( K i 1.7 μ M ). This compound had only a modest effect on feeding. The other Y 5 ‐preferring peptide [cPP 1–7 ,NPY 19–23 ,Ala 31 ,Aib 32 ,Gln 34 ]hPP had a higher affinity at the Y 5 receptor ( K i 1.32 n M ) and also at the Y 1 receptor ( K i 85 n M ). It potently stimulated feeding: the food consumption after administration of this peptide was two‐fold compared to NPY. Our results support the view that both the receptor subtypes Y 1 and Y 5 are involved in the stimulation of feeding. As the action profiles of the Y 1 and Y 5 agonists on feeding parameters were different, it seems that they influence different phases of eating.British Journal of Pharmacology (2003) 139 , 1433–1440. doi: 10.1038/sj.bjp.0705389