NOVEL MODIFIED CARBOXY-TERMINAL FRAGMENTS OF NEUROPEPTIDE-Y WITH HIGH-AFFINITY FOR Y-2-TYPE RECEPTORS AND POTENT FUNCTIONAL ANTAGONISM AT A Y-1-TYPE RECEPTOR

• Published in: Journal of medicinal chemistry Vol. 38; no. 7; pp. 1150 - 1157
• Main Authors: LEBAN, JJ, HEYER, D, LANDAVAZO, A, MATTHEWS, J, AULABAUGH, A, DANIELS, AJ
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 31.03.1995
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; DESIGN; PEPTIDES; HORMONE; PROTEIN; SOLID-PHASE SYNTHESIS; ANALOGS; ADENYLATE-CYCLASE; BINDING; BRAIN; POLYPEPTIDE
• ISSN: 0022-2623
• 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 Y-2 (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 Y-1 (human erythroleukemia (HEL) cell; ED(50) = 8.8 +/- 0.5 nM) receptors with potency comparable to that of NPY(1-36) (ED(50) = 5 nM). Molecular dynamics and H-1-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 PILL 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 Y-2 affinity. This potent antagonist may provide further insight into the physiological role(s) for NPY in the mammalian and peripheral nervous system.