Centrally truncated neuropeptide Y analog acts as an agonist for Y1 receptors on SK-N-MC cells.

The similarity of neuropeptide Y (NPY) to pancreatic polypeptide (PP), whose X-ray crystallographic structure is known, has allowed computer-assisted molecular modelling of NPY and predictions of its three-dimensional structure. Utilizing these techniques, Krstenansky et al. (Proc. Natl. Acad. Sci. U.S.A., 86 (1989) 4377-4381) reported that a centrally truncated analog of porcine NPY, [D-Cys7-Aoc8-17-Cys20]pNPY, which was designed to maintain the tertiary structure of the native molecule, bound to sites on membranes from mouse brain with even higher affinity than native NPY. As brain membranes may represent a heterogeneous mixture of receptor subtypes, we decided to characterize the activity of this analog on a defined cell line. SK-N-MC cells are a human epithelioma cell line with high-affinity receptors of the Y1 subtype which are coupled to inhibition of adenylate cyclase. (D-Cys7-Aoc8-17-Cys20]pNPY bound to receptors on SK-N-MC cells, but in contrast to membranes from mouse brain, with a lower affinity than pNPY. Furthermore, [D-Cys7-Aoc8-17-Cys20]pNPY was able to inhibit isoproterenol-stimulated cAMP production in these cells. Therefore, it appears that the central amino acids deleted from this analog are not involved in NPY binding, and biological activity can be maintained by conservation of the tertiary structure of NPY around the binding surface.