Structure-activity analysis of N-acetyl [Leu(28,31)] NPY 24-36: a potent neuropeptide Y Y(2) receptor agonist.
Neuropeptide Y (NPY) and a C-terminal analog of NPY, N acetyl [Leu(28,31)] NPY 24-36, act at NPY Y(2) receptors to potently inhibit cardiac vagal activity. The C-terminal analog is equipotent as NPY in inhibiting cardiac vagal activity but does not retain any pressor or Y(1) activity. This study investigates the importance of each amino acid in the 13 residue analog for functional activity by systematically substituting each residue with L-alanine. The inhibitory effect on cardiac vagal action decreased with substitution at residues 25,26,28,29 and 31. No decrease in activity was observed with alanine substitution at residues 24, 27 or 30. Residues 32 and 34 retained activity only at high doses, while residues 33, 35 and 36 were not active following alanine substitution. The difference in potency of the effective analogs suggests secondary structure of the peptide is as important for activity as retaining key amino acids.
Smith-White
M A
MA
Prince of Wales Medical Research Institute, Randwick, Sydney, Australia. m.smith-white@unsw.edu.au
Potter
E K
EK
D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine; D004305:Dose-Response Relationship, Drug; D005260:Female; D008239:Lysine; D009433:Neural Inhibition / Q000187:drug effects; D009478:Neuropeptide Y / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014630:Vagus Nerve / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology
D009478:Neuropeptide Y; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; C084653:neuropeptide Y (24-36), Ac-(Leu(28,31))-; C095889:neuropeptide Y2 receptor; D001120:Arginine; D008239:Lysine