Structure-Activity Relationships of Neuromedin U. III. Contribution of Two Phenylalanine Residues in Dog Neuromedin U-8 to the Contractile Activity

概要

論文の詳細を見る
Dog neuromedin U-8 (d-NMU-8; pGlu-X^2-Leu-Y^4-Arg-Pro-Arg-Pro-Arg-Asn-NH_2,X=Y=Phe) has potent biological activity to stimulate an isolated chicken crop smooth muscle preparation with the relative activity (RA value) of 5.78 to porcine neuromedin U-8 (p-NMU-8). To elucidate the contribution of the two phenylalanine residues of NMU-8 to the biological activity, fourteen d-NMU-8 analogs modified either at positio 2 or 4,[X^2]- or [Y^4]-d-NMU-8,were synthesized, where X and Y were Ala, Tyr, Trp, Thr, Glu, His or cyclohexylalanine (Cha).Most of the analogs retained very low contractile activity, suggesting the importance of both Phe residues in d-NMU-8 for the biological activity. [X^2]-d-NMU-8 analogs had lower biological activity in terms of the RA value than the corresponding [Y^4]-d-NMU-8,when X and Y are the same amino acid. Loss of aromaticity of Phe^2([Cha^2]-d-NMU-8) resulted in a marked decrease of the contractile activity, while that of Phe^4 ([Cha^4]-d-NMU-8)resulted in retention of considerable activity, with the RA value of 2.68. [Tyr^4]-d-NMU-8 was an exceptional analog with higher contractile activity (p<0.01) than the parent compound d-NMU-8,having the RA value of 12.6. The results indicated that the aromatic side chain of the Phe residue at position 2 contribues more than that at position 4 to the biological activity.
公益社団法人日本薬学会の論文
1996-10-15