Guerrini R, Calo' G, Bigoni R, Rizzi D, Regoli D, Salvadori S
Department of Pharmaceutical Sciences and Biotechnology Center, Ferrara, Italy.
J Pept Res. 2001 Mar;57(3):215-22. doi: 10.1111/j.1399-3011.2001.00820.x.
A series of analogs of the ORL1 receptor antagonist [Nphe1]-NC(1-13)-NH2 was prepared and tested for agonistic and antagonistic activities in the mouse vas deferens, a preparation that shows high sensitivity to nociceptin and related peptides. The purpose of this study was to determine the role of the aromatic residue at the N-terminal for antagonism and eventually identify compounds with improved potency. Results indicated that all 23 compounds are inactive as agonists, and the antagonistic potency of the initial template [Nphe1]-NC(1-13)-NH2 is high (pKB 6.43) compared with those of all other compounds except [(S)(betaMe)Nphe1]NC(1-13)-NH2 (pK(B) 6.48). The other 22 compounds can be divided into two groups: 10 show antagonistic potencies (pK(B)) ranging from 5.30 to 5.86, whereas the other 12 compounds are inactive. This study clearly shows that the aromatic ring of Nphe is very critical for the interaction with the ORL1 receptor and can not be enlarged or sterically modified without significant loss of antagonistic potency.
制备了一系列ORL1受体拮抗剂[Nphe1]-NC(1-13)-NH2的类似物，并在小鼠输精管中测试其激动和拮抗活性，该制剂对孤啡肽及相关肽表现出高敏感性。本研究的目的是确定N端芳香族氨基酸残基在拮抗作用中的作用，并最终鉴定出效力提高的化合物。结果表明，所有23种化合物均无激动剂活性，初始模板[Nphe1]-NC(1-13)-NH2的拮抗效力较高（pKB 6.43），与除[(S)(βMe)Nphe1]NC(1-13)-NH2（pK(B) 6.48）之外的所有其他化合物相比。其他22种化合物可分为两组：10种表现出5.30至5.86的拮抗效力（pK(B)），而其他12种化合物无活性。本研究清楚地表明，Nphe的芳香环对于与ORL1受体的相互作用非常关键，并且在不显著丧失拮抗效力的情况下不能扩大或进行空间修饰。
