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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-NH(2)](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-NH(2) using various diamino-dicarboxylic acids containing either di-, tri-, or tetramethylene 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.

Type Journal
ISBN 0022-2623 (Print)
Authors Balasubramaniam, A.;Mullins, D. E.;Lin, S.;Zhai, W.;Tao, Z.;Dhawan, V. C.;Guzzi, M.;Knittel, J. J.;Slack, K.;Herzog, H.;Parker, E. M. :
Responsible Garvan Author Prof Herbert Herzog
Published Date 2006-01-01
Published Volume 49
Published Issue 8
Published Pages 2661-5
Status Published in-print
URL link to publisher's version