Structure-affinity relationships of C-terminal cyclic analogue of neuropeptide Y for the Y1-receptor.
We previously reported that a cyclic octapeptide amide, c[D-Cys29, Cys-34]NPY Ac-29-36 (YM-42454) showed a high affinity for Y1-receptors in SK-N-MC cells (Ki=0.047,microM) but not for Y2-receptors in the porcine hippocampus membranes (Ki>10microM). To explore the critical residues of this unique cyclic peptide for Y1-binding activity, the structure-affinity relationships were investigated by means of amino acid replacement. The results indicated that the hydrophobic side-chains of Leu30 and Ile31, the guanidinium groups of Arg33 and Arg33, and the C-terminal amide are critical for the binding affinity of YM-42454 to the Y1-receptor. On the other hand, Thr32 in YM-42454 might not be critical for the Y1-binding affinity. 1H-NMR studies for YM-42454 and its derivatives have suggested that the critical residues are involved in the direct interaction with a Y1-receptor rather than in maintaining the bioactive conformation.
Takebayashi
Y
Y
Lead Discovery Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co, Ltd, Ibaraki, Japan. takebaya@yamanouchi.co.jp
Koga
H
H
Togami
J
J
Kurihara
H
H
Furuya
T
T
Tanaka
A
A
Murase
K
K
D000818:Animals; D003500:Cyclization; D006801:Humans; D008279:Magnetic Resonance Imaging; D009478:Neuropeptide Y / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D017476:Receptors, Neuropeptide Y / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine; D014316:Tritium; D014407:Tumor Cells, Cultured
D009478:Neuropeptide Y; D010456:Peptides, Cyclic; D017476:Receptors, Neuropeptide Y; C423466:YM 42454; C097212:neuropeptide Y-Y1 receptor; D014316:Tritium