Bis(31/31′){[Cys31,Nva34]NPY(27-36)-NH2}:: a neuropeptide Y (NPY) Y5 receptor selective agonist with a latent stimulatory effect on food intake in rats

The actions of neuropeptide Y (NPY) are mediated by at least six G-protein coupled receptors denoted as Y-1, Y-2, Y-3, Y-4, Y-5, and y(6). Investigations using receptor selective ligands and receptor knock-out mice suggest that NPY effects on feeding are mediated by both Y-1 and Y-5 receptors. We have previously shown that Cys-dimers of NPY C-terminal peptides exhibit Y-1 selectivity relative to Y-2 receptors. Re-investigation of their selectivity with respect to the newly cloned receptors, has identified bis(31/31') {[Cys(31), Nva(34)]NPY(27-36)-NH2} (BWX-46) as a Y-5 receptor selective agonist. BWX-46 selectively bound Y-5 receptors, and inhibited cAMP synthesis by Y-5 cells with potencies comparable to that of NPY. Moreover, BWX-46 (10 muM) exhibited no significant effect on the cAMP synthesis by Y-1, Y-2, and Y-4 cells. Thus, BWX-46 constitutes the lowest molecular weight Y-5 selective agonist reported to date. Intrahypothalamic (iht)-injection of 30 and 40 mug of BWX-46 stimulated the food intake by rats in a gradual manner, reaching maximal level 8 h after injection. This response was similar to that exhibited by other Y-5 selective agonists, but differed from that of NPY, which exhibited a rapid orexigenic stimulus within 1 h. It is suggested that the differences in the orexigenic stimuli of NPY and Y-5 agonists may be due to their differences in the signal transduction mechanisms. (C) 2002 Elsevier Science Inc. All rights reserved.