Structure-Affinity Relationships of C-terminal Cyclic Analogue of Neuropeptide Y for the Y₁-Receptor

Abstract

We previously reported that a cyclic octapeptide amide, c[D-Cys²⁹, Cys³⁴]NPY Ac-29-36 (YM-42454) showed a high affinity for Y₁-receptors in SK-N-MC cells (K_i=0.047μM) but not for Y₂-receptors in the porcine hippocampus membranes (K_i>10μM). 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 Arg³⁵, 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.