Novel Modified Carboxy Terminal Fragments of Neutropeptide Y with High Affinity for Y2-Type Receptors and Potent Functional Antagonism at a Y1-Type Receptor

Article abstract of DOI:10.1021/jm00007a012

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.