Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36):: Development of an anorectic Y4 receptor selective agonist with picomolar affinity

We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH2](2), 1, to be a moderately selective neuropeptide Y (NPY) Y-4 receptor agonist. Toward improving the selectivity and potency for Y-4 receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH2 using various diamino-dicarboxylic acids containing either di, tri-, or tetra triethyl e ne spacers. These parallel dimers, 2A, 2B, 3, 4A, and 4B, and the corresponding linear tandem dimer and trimer analogues, 5 and 6, had enhanced selectivity and affinity for Y-4 receptors compared to 1 (Table 1). Substitution of Trp and Nva with Tyr and Leu, respectively, as in 2,7-D/L-diaminosuberic acid derivatized dimer, 7, resulted in a superior Y-4 selective agonist with picomolar affinity. Intraperitoneal (ip) injection of 7 potently inhibited food intake in fasted mice. Moreover, 7 (ip) inhibited the food intake in wild-type mice and not in Y-4(-/-) knock-out mice, confirming that the actions of 7 on food intake are not due to global effects, but specifically mediated Y-4 receptors.