Synthesis, Structure, and Antagonistic Properties of des-Asn 29 [ d -Trp 28,32 ]NPY(27–36)

Bis(31/31‘){[Cys31,Trp32,Nva34]NPY- (31−36)}: A Specific NPY Y-1 Receptor Antagonist

“…11 Further structure-activity studies resulted in the development of Y-1 receptor antagonists, Des-Asn 29 [D-Trp 28,32 ]-NPY(27-36) (K i for Y-1 > 10 000 nM) and Des-Asn 29 [D-Trp 28,32 ,Nva 34 ]NPY(27-36) (K i for Y-1 ) 328 ( 86 nM). 12,13 Although we speculated that the turn structures induced by both D-Trp 28 and D-Trp 32 may be crucial to imparting antagonistic properties, solution NMR studies revealed the existence of two quasihelical loop structures rather than β-turns. 12,13 Therefore, we synthesized and investigated the properties of Des-Asn 29 [Trp 28,32 ,Nva 34 ]NPY (27)(28)(29)(30)(31)(32)(33)(34)(35)(36).…”

“…11 Subsequent investigations led to the development of Des-Asn 29 [D-Trp 28,32 ,Nva 34 ]NPY(27-36) and Des-Asn 29 [ Trp 28,32 ,Nva 34 ]NPY(27-36). 12,13 On the basis of these findings, we have now developed specific NPY Y-1 receptor antagonists, and these results are described in this communication.…”

“…[3][4][5][6][7][8][9][10] Although most of these compounds were either weak or nonselective, the two non-peptide antagonists reported recently appear to have promising properties. 9,10 Recently, we reported that centrally truncated analogs of ]NPY 4 such as Des-AA [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]32 ,Aoc 6 ]-NPY antagonized NPY-induced mobilization of intrac-…”

“…15 Since the hypothalamic NPY receptor antagonist, [D-Trp 32 ]NPY 4 , did not bind to Y-1 receptors, we synthesized similar truncated analogs of ]NPY and demonstrated that these analogs antagonized NPY effects on [Ca 2+ ] i in HEL cells. 11 One of these analogs, Des-AA [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] [D-Ala 5 ,D-Trp 32 ,Aoc 6 ]NPY, was also shown to antagonize NPY-induced hypertension in rats. 11 Further structure-activity studies resulted in the development of Y-1 receptor antagonists, Des-Asn 29 [D-Trp 28,32 ]-NPY(27-36) (K i for Y-1 > 10 000 nM) and Des-Asn 29 [D-Trp 28,32 ,Nva 34 ]NPY(27-36) (K i for Y-1 ) 328 ( 86 nM).…”

“…Although this peptide retained the antagonistic property, neither the affinity (K i for Y-1 ) 359 ( 93 nM) nor the selectivity for Y-1 receptors increased compared to those of its D-Trp counterpart. 12,13 2D NMR studies revealed that NPY exists as a dimer in solution with predominantly an R-helical structure in the C-terminal 11-36 region. [16][17][18] This observation and the presence of helical structures in our antagonists led us to speculate that dimerization of our antagonists may enhance the receptor affinity via the stabilization of the helical structures.…”