Hashimoto T, Kurosawa K, Sakura N
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Chem Pharm Bull (Tokyo). 1995 Jul;43(7):1154-7. doi: 10.1248/cpb.43.1154.
To develop a highly potent agonist and to examine the structure-contractile activity relationship of neuromedin U-8(NMU-8), seventeen analogs were synthesized and tested for contractile activity on isolated chicken crop smooth muscle preparations. The analogs were designed to examine the contributions of cyclic structure and acidic function at the N-terminal of NMU-8 and NMU-8(2--8) to the biological activity. The relative activity (RA) values of NMU-8 analogs were as follows: [Dp-Glu1]-NMU-8,5.50; [pyrohomoglutamyl(pHgu)1]-NMU-8,4.65;[D-pHgu1]-NMU-8, 4.66; [Asp1]-NMU-8, 11.4; [acetyl(Ac)-Asp1]-NMU-8, 9.81; [Ac-Glu1]- NMU-8, 18.6; [succinyl (Suc)-Tyr1-NMU-8,69.3; [3-sulfoalanyl (Sal)1]-NMU-8, 12.7. The RA values of NMU-8(2--8) analogs were as follows: alpha-picolinyl (Pic)-NMU-8 (2--8), 7.96; 2-furoyl (Fur)-NMU-8, (2--8), 9.91; 2-thiophenecarboxyl (Thi)-NMU-8 (2--8), 3.41; 4-hydroxyphenylpropionyl (Hpp)-NMU-8(2--8), 3.20; o-phthalyl (Pht)-NMU-8 (2--8), 11.3; Suc-NMU-8 (2--8), 109; malonyl (Mlo)-NMU-8 (2--8), 17.9; maleyl (Mle)-NMU-8 (2--8), 31.6; glutaryl (Glt)-NMU-8 (2--8), 81.3; The potencies of the analogs were higher than that of p-NMU-8. Suc-NMU-8 (2--8) showed the highest potency among the analogs synthesized. The results reveal that the carboxylic acid group at the N-terminus of NMU-8 makes a major contribution to the activity.
为开发一种高效激动剂并研究神经介素U-8（NMU-8）的结构-收缩活性关系，合成了17种类似物，并在离体鸡嗉囊平滑肌标本上测试其收缩活性。这些类似物旨在研究NMU-8和NMU-8（2-8）的环状结构以及N端酸性官能团对生物活性的贡献。NMU-8类似物的相对活性（RA）值如下：[Dp-Glu1]-NMU-8，5.50；[焦谷氨酸（pHgu）1]-NMU-8，4.65；[D-pHgu1]-NMU-8，4.66；[Asp1]-NMU-8，11.4；[乙酰基（Ac）-Asp1]-NMU-8，9.81；[Ac-Glu1]-NMU-8，18.6；[琥珀酰（Suc）-Tyr1-NMU-8，69.3；[3-磺基丙氨酰（Sal）1]-NMU-8，12.7。NMU-8（2-8）类似物的RA值如下：α-吡啶基（Pic）-NMU-8（2-8），7.96；2-呋喃甲酰基（Fur）-NMU-8，（2-8），9.91；2-噻吩甲酰基（Thi）-NMU-8（2-8），3.41；4-羟基苯丙酰基（Hpp）-NMU-8（2-8），3.20；邻苯二甲酰基（Pht）-NMU-8（2-8），11.3；Suc-NMU-8（2-8），109；丙二酰基（Mlo）-NMU-8（2-8），17.9；马来酰基（Mle）-NMU-8（2-8），31.6；戊二酰基（Glt）-NMU-8（2-8），81.3；这些类似物的效力高于对-硝基-NMU-8。Suc-NMU-8（2-8）在合成的类似物中显示出最高的效力。结果表明，NMU-8 N端的羧酸基团对活性起主要作用。
