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.
Balasubramaniam
Ambikaipakan
A
Division of Gastrointestinal Hormones, Department of Surgery and Interdisciplinary Neurosciences Program, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA. Ambi.Bala@uc.edu
Mullins
Deborra E
DE
Lin
Shu
S
Zhai
Wexiu
W
Tao
Zhiyong
Z
Dhawan
Vikas C
VC
Guzzi
Mario
M
Knittel
James J
JJ
Slack
Katy
K
Herzog
Herbert
H
Parker
Eric M
EM
D000818:Animals; D001067:Appetite Depressants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004435:Eating; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017476:Receptors, Neuropeptide Y / Q000819:agonists*; D013329:Structure-Activity Relationship
D001067:Appetite Depressants; D009479:Neuropeptides; D009842:Oligopeptides; D017476:Receptors, Neuropeptide Y; C510303:tyrosyl-arginyl-leucyl-arginyl-tyrosinamide 2,7-diaminosuberic acid dimer; C109491:neuropeptide Y4 receptor