Novel modified carboxy terminal fragments of neuropeptide 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
J J
JJ
Division of Organic Chemistry, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709, USA.
Heyer
D
D
Landavazo
A
A
Matthews
J
J
Aulabaugh
A
A
Daniels
A J
AJ
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002942:Circular Dichroism; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D002118:Calcium