Peptide ligands

Over the past four years there’s been considerable progress in the development of novel selective analogs of NPY. A number of these analogs have been directed toward discovering tools to understand the role of the Y1 and Y5 receptors in the feeding produced by central administration of NPY. For instance, several novel analogs of NPY have been found to be highly selective for the Y1 receptor. These all produce an increase in feeding after intracerebroventricular administration. Over 4h, [D-Arg25]-NPY produced a similar increase in feeding compared to NPY. This increase in feeding was blocked by the peptidic Y1 antagonist 1229U91. However, it was found that 1229U91, besides being a Y1 antagonist, also is a potent agonist at the Y4 receptor. Soll and co-workers have reported a very potent and Y1 selective peptide [Phe7, Pro34]-NPY, though no work has been reported on its effects in vivo. In addition to novel Y1 receptor agonists, an analog of the Y1 selective peptide antagonist 1229U91 was recently reported. This analog consisted of an OMe replacement for the amide in 1229U91 (GR231118). This peptide retained high affinity for the Y1 receptor but had much reduced affinity for the Y4 receptor when compared to 1229U91. In functional assays, this peptide analog potently antagonized the NPY inhibition of forskolin-stimulated adenylate cyclase in Y1 receptor containing cells while having no effect (agonist or antagonist) in Y4 receptor containing cells. When administered intrahypothalamically, this Y1 antagonist inhibited both NPY stimulated feeding as well as feeding in schedule fed rats.

More limited work has been performed to obtain Y2 selective peptide analogs. One of the more promising peptide analogs was recently published by Soll et al. This peptide (Cyclo S-S [Cys20, Cys24]pNPY) exhibits subnanomolar affinity for the Y2 receptor with low micromolar affinity at Y1 and Y5. No additional information is available in the scientific literature that further describes the properties of this compound. On the other hand, considerable progress has been made for developing Y5 selective agonists. However, several of these peptide analogs have considerable affinity for both the Y4 and Y5 receptors. One of these analogs, 2-36[K4, RYYSA19-23]-PP, produced a dose-dependent increase in food consumption after intracerebroventricular administration. The magnitude of this increase in food intake exceeded that produced by identical doses of NPY. More selective Y5 agonist peptides have also been reported that have little affinity for the Y4 receptor. One of these, [Ala31, Aib32]-NPY was found to produce a small increase in food intake when compared to control animals. Another analog, [cPP1-7, NPY19-23, Ala31, Aib32, Gln34]-hPP, which exhibited an approximately 20-fold higher affinity for the Y5 receptor when compared to analog [Ala31, Aib32]-NPY, produced increases in food intake that exceeded NPY at similar doses. Finally, the relatively low affinity analog, p[D-Trp34]-NPY, was reported to be a selective Y5 agonist. This peptide produced a similar inhibition of forskolin-stimulated adenylate cyclase to that seen for NPY and was found to increase food intake after intracerebroventricular administration. However, the increase was not as substantial is that observed with similar doses of NPY. The putative Y5 selective antagonist, CGP71683A, antagonized the increase in food intake produced by this peptide, however, the specificity of CGP71683A has recently been called into question.


Zukowska, Z., & Feuerstein, G. Z. (Eds.). (2006). The NPY Family of Peptides in Immune Disorders, Inflammation, Angiogenesis, and Cancer. Springer Science & Business Media.