高亲和力速激肽NK2受体拮抗剂的合理设计。

Rational design of high affinity tachykinin NK2 receptor antagonists.

作者信息

Boyle S, Guard S, Hodgson J, Horwell D C, Howson W, Hughes J, McKnight A, Martin K, Pritchard M C, Watling K J

机构信息

Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge, U.K.

出版信息

Bioorg Med Chem. 1994 Feb;2(2):101-13. doi: 10.1016/s0968-0896(00)82006-4.

DOI:10.1016/s0968-0896(00)82006-4

PMID:7922121

Abstract

The rational discovery of a high affinity NK2 receptor antagonist is described utilizing a general strategy for peptoid design. The contribution to NK2 receptor binding affinity for each amino acid of the hexapeptide 'minimum fragment': Leu-Met-Gln-Trp-Phe-GlyNH2 (8c), was examined by preparing derivatives where each amino acid in turn was replaced with Ala in an 'alanine scan'. The results from this study indicated the primary importance of the Trp and Phe side-chain for binding and led to the observation that Z-Trp-PheNH2 (9a) is a micromolar affinity NK2 receptor dipeptide lead. Further exploration of structure-affinity via conformationally restricted analogues and N- and C-terminus modifications gave a selective, nanomolar affinity NK2 receptor antagonist, (2,3di-CH3OPh)CH2OCO(S)Trp(S)alpha-MePheGlyNH2, PD 147714 (19) with an K(i) = 1.4 nM (hamster urinary bladder membranes and using [125I]-iodohistidyl-NKA (0.1 nM) as the radioligand).

摘要

利用类肽设计的通用策略描述了高亲和力NK2受体拮抗剂的合理发现。通过制备衍生物，其中六肽“最小片段”Leu-Met-Gln-Trp-Phe-GlyNH2（8c）中的每个氨基酸依次被Ala取代，进行“丙氨酸扫描”，研究了每个氨基酸对NK2受体结合亲和力的贡献。该研究结果表明色氨酸和苯丙氨酸侧链对结合至关重要，并导致观察到Z-Trp-PheNH2（9a）是一种具有微摩尔亲和力的NK2受体二肽先导物。通过构象受限类似物以及N端和C端修饰对结构-亲和力进行进一步探索，得到了一种选择性的、具有纳摩尔亲和力的NK2受体拮抗剂(2,3-二甲基氧苯基)CH2OCO(S)Trp(S)α-甲基苯丙氨酸甘氨酰胺，PD 147714（19），其K(i)=1.4 nM（仓鼠膀胱膜，使用[125I]-碘组氨酰-NKA（0.1 nM）作为放射性配体）。