@article {Mullins534, author = {Deborra Mullins and Dean Kirby and Joyce Hwa and Mario Guzzi and Jean Rivier and Eric Parker}, title = {Identification of Potent and Selective Neuropeptide Y Y1 Receptor Agonists with Orexigenic Activity in Vivo}, volume = {60}, number = {3}, pages = {534--540}, year = {2001}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Neuropeptide Y (NPY) binds to a family of G-protein coupled receptors termed Y1, Y2, Y3, Y4, Y5, and y6. The use of various receptor subtype-selective agonists and antagonists has facilitated identification of the receptor subtypes responsible for mediating many of the biological effects of NPY. For example, the potent orexigenic activity of NPY is believed to be mediated by both the Y1and Y5 receptor subtypes. Several selective Y5receptor agonists that stimulate food intake in rodents are available, but no selective Y1 receptor agonist has been reported. We have identified several NPY analogs that bind the NPY Y1receptor with high affinity and exhibit full agonist activity, measured as inhibition of forskolin-stimulated cAMP production in cells expressing the cloned NPY Y1 receptor. [d-Arg25]-NPY, [d-His26]-NPY, Des-AA10{\textendash}17[Cys7,21,Pro34]-NPY, Des-AA11{\textendash}18[Cys7,21,d-Lys9(Ac)]-NPY, Des-AA11{\textendash}18[Cys7,21,d-Lys9(Ac),Pro34]-NPY, Des-AA11{\textendash}18[Cys7,21,d-Lys9(Ac),d-His26]-NPY and Des-AA11{\textendash}18[Cys7,21,d-Lys9(Ac),d-His26, Pro34]-NPY bind the NPY Y1 receptor with Kivalues of 0.9 {\textpm} 0.2, 2.0 {\textpm} 0.3, 0.2 {\textpm} 0.05, 0.7 {\textpm} 0.1, 0.2 {\textpm} 0.01, 2.2 {\textpm} 0.3, and 1.2 {\textpm} 0.3 nM, respectively, and inhibit forskolin-stimulated cAMP production with EC50 values of 0.2 {\textpm} 0.02, 0.5 {\textpm} 0.04, 0.3 {\textpm} 0.03, 0.5 {\textpm} 0.05, 0.4 {\textpm} 0.16, 5.3 {\textpm} 0.32, and 5.1 {\textpm} 0.97 nM, respectively. These peptides are highly selective for the NPY Y1 receptor relative to the NPY Y2, Y4, and Y5 receptors. [d-Arg25]-NPY, [d-His26]-NPY and Des-AA11{\textendash}18[Cys7,21, d-Lys9(Ac),d-His26,Pro34]-NPY stimulate food intake dose-responsively in Long-Evans rats for at least 4 h after intracerebroventricular administration. Although the involvement of Y1 receptors in several physiological activities, such as vasoconstriction and anxiolysis, remains to be investigated, adequate tools are now available. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/60/3/534}, eprint = {https://molpharm.aspetjournals.org/content/60/3/534.full.pdf}, journal = {Molecular Pharmacology} }