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-AA^10–17[Cys^7,21,Pro³⁴]-NPY, Des-AA^11–18[Cys^7,21,d-Lys⁹(Ac)]-NPY, Des-AA^11–18[Cys^7,21,d-Lys⁹(Ac),Pro³⁴]-NPY, Des-AA^11–18[Cys^7,21,d-Lys⁹(Ac),d-His²⁶]-NPY and Des-AA^11–18[Cys^7,21,d-Lys⁹(Ac),d-His²⁶, Pro³⁴]-NPY bind the NPY Y₁ receptor with K_ivalues of 0.9 ± 0.2, 2.0 ± 0.3, 0.2 ± 0.05, 0.7 ± 0.1, 0.2 ± 0.01, 2.2 ± 0.3, and 1.2 ± 0.3 nM, respectively, and inhibit forskolin-stimulated cAMP production with EC₅₀ values of 0.2 ± 0.02, 0.5 ± 0.04, 0.3 ± 0.03, 0.5 ± 0.05, 0.4 ± 0.16, 5.3 ± 0.32, and 5.1 ± 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-AA^11–18[Cys^7,21, 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.