Folkers K, Feng D M, Asano N, Håkanson R, Weisenfeld-Hallin Z, Leander S
Institute for Biomedical Research, University of Texas, Austin 78712.
Proc Natl Acad Sci U S A. 1990 Jun;87(12):4833-5. doi: 10.1073/pnas.87.12.4833.
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.
斯帕替德（D-精氨酸1-脯氨酸2-赖氨酸3-脯氨酸4-谷氨酰胺5-谷氨酰胺6-D-色氨酸7-苯丙氨酸8-D-色氨酸9-亮氨酸10-亮氨酸11-氨基）于1984年被引入作为速激肽拮抗剂，并已成为设计新拮抗剂的起点，这些新拮抗剂已被证明更有效且无神经副作用。最显著且不可预测的结构变化是通过将谷氨酰胺6变为天冬酰胺6来删除一个亚甲基，这显著提高了效力。基于斯帕替德的D-精氨酸1和赖氨酸3会导致神经副作用，许多新设计产生了D-赖氨酸（烟酰胺）1-脯氨酸2-3-（3-吡啶基）丙氨酸3-脯氨酸4-3,4-二氯-D-苯丙氨酸5-天冬酰胺6-D-色氨酸7-苯丙氨酸8-D-色氨酸9-亮氨酸10-正亮氨酸11-氨基[斯帕替德II，其中D-赖氨酸（烟酰胺）是Nε-烟酰赖氨酸，3-（3-吡啶基）丙氨酸是Pal(3)，3,4-二氯-D-苯丙氨酸是D-Phe(Cl2)，正亮氨酸是Nle]，它是一种无神经毒性的强效拮抗剂。斯帕替德II是一种十一肽，在P物质序列中共有七个取代基，由两个天然L氨基酸、一个非天然L氨基酸和四个非天然D氨基酸组成。比较P物质和斯帕替德II的π键和σ键氨基酸取代基，以便未来了解作用机制和抑制结合的必需取代基。斯帕替德II有五个π键和六个σ键氨基酸部分，而P物质有两个π键和九个σ键部分。
