Novel Modified Carboxy Terminal Fragments of Neutropeptide Y with High Affinity for Y2-Type Receptors and Potent Functional Antagonism at a Y1-Type Receptor
Peptide analogs of neuropeptide Y (NPY) with a Tyr-32 and Leu-34 replacement resulted in the decapeptide TyrIleAsnLeuIleTyrArgLeuArgTyr-NH2 (9; Table 1) and a 3700-fold improvement in affinity at Y2 (rat brain; IC50 = 8.2 +/- 3 nM) receptors when compared to the native NPY(27-36) C-terminal fragment.In addition, compound 9 was an agonist at Y1 (human erythroleukemia (HEL) cell; ED50 = 8.8 +/- 0.5 nM) receptors with potency comparable to that of NPY(1-36) (ED50 = 5 nM).Molecular dynamics and 1H-NMR were used to propose a solution structure of decapeptide 9 and for subsequent analog design.The replacement of Leu with Pro at position 4 of decapeptide 9 afforded an antagonist of NPY in HEL cells (18, TyrIleAsnProIleTyrArgLeuArgTyr-NH2; IC50 = 100 +/- 5 nM).Deletion of the N-terminal tyrosine of 18 resulted in a 10-fold improvement in antagonistic activity with a parallel 4-fold decrease in Y2 affinity.This potent antagonist may provide further insight into the physiological role(s) for NPY in the mammalian and peripheral nervous system.
Leban, Johann J.,Heyer, Dennis,Landavazo, Antonio,Matthews, Jessica,Aulabaugh, Ann,Daniels, Alejandro J.
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