期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1990
卷号：87
期号：12
页码：4833-4835
DOI：10.1073/pnas.87.12.4833
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Spantide (D-Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-D-Trp7-Phe8-D-Trp9-++ +Leu10-Leu11-NH2) was introduced as a tachykinin antagonist in 1984 and has served as a starting point in the design of new antagonists that have proven to be more effective and have exhibited no neurological side effects. The most remarkable and unpredictable structural change that significantly increased potency was deletion of a methylene group by changing Gln6 to Asn6. On the basis that D-Arg1 and Lys3 of spantide contribute to neurological side effects, many new designs led to D-Lys(Nic)1-Pro2-Pal(3)3-Pro4-D-Phe(Cl2)5-Asn6-D-Trp7-Phe8-D-Trp9- Leu10-Nle11- NH2 [spantide II, where D-Lys(Nic) is N epsilon-nicotinoyllysine, Pal(3) is 3-(3-pyridyl)alanine, D-Phe(Cl2) is 3,4-dichloro-D-phenylalanine, and Nle is norleucine], which is a potent antagonist without neurotoxicity. Spantide II, an undecapeptide, has a total of seven substitutions in the sequence of substance P, consisting of two natural L amino acids, and one unnatural L amino acid, and four unnatural D amino acids. The pi- and sigma-bond amino acid substituents of substance P and spantide II are compared toward a future understanding of the essential substituents for mechanism and inhibition binding. Spantide II has five pi-bond and six sigma-bond amino acid moieties, and substance P has two pi-bond and nine sigma-bond moieties.
