Somatostatin receptor 1 selective analogues: 4. Three-dimensional consensus structure by NMR
Somatostatin receptor 1 selective analogues: 4. Three-dimensional consensus structure by NMR
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DOI：
10.1021/jm049518u
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发表时间：
2005-01-27
影响因子：
7.3
通讯作者：
Riek, R
中科院分区：
文献类型：
--
作者：
Grace, CRR;Durrer, L;Riek, R
描述了生长抑素（SRIF）的六种类似物的三维核磁共振结构。这些氨基酸4-（n-异丙基）-氨基甲基苯基丙氨酸（IAmp）位于9位的类似物与人类SRIF亚型I受体具有强效和高选择性结合。构象表明，这些类似物的骨架具有类似于sst(2)亚型选择性类似物的发夹状结构。该结构作为支架，用于保持D-Trp(8)、lAmp(9)、Phe(7)和Phe（11）或m-I-Tyr(11) （m-I-Tyr =单碘酪氨酸）侧链的独特排列。这些类似物的构象偏好和生物学分析结果（1,2）允许对SRIF的结构-活性关系进行详细的研究。sst(1)选择性类似物的共识药效团要求吲哚/2-萘环、IAmp侧链和两个芳香环之间有一组独特的距离。该基序对于解释所研究的所有类似物的结合亲和力是必要和充分的，并且与现有的sst(4)以及sst(2)/sst(5)选择性模型不同。
The three-dimensional NMR structures of six analogues of somatostatin (SRIF) are described. These analogues with the amino acid 4-(N-isopropyl)-aminomethylphenylalanine (IAmp) at, position 9 exhibit potent and highly selective binding to human SRIF subtype I receptors The conformations reveal that the backbones of these analogues have a hairpin-like structure similar to the sst(2)-subtype-selective analogues. This structure serves as a scaffold for retaining a unique arrangement of the side chains Of D-Trp(8), lAmp(9), Phe(7), and Phe(11) or m-I-Tyr(11) (m-I-Tyr = mono-iodo-tyrosine). The conformational preferences and results from biological analyses of these analogues(1,2) allow a detailed study of the structure- activity relationship of SRIF. The proposed consensus pharmacophore of the sst(1)-selective analogues requires a unique set of distances between an indole/2-naphthyl ring, an IAmp side chain, and two aromatic rings. This motif is necessary and sufficient to explain the binding affinities of all of the analogues studied and is distinct from the existing models suggested for sst(4) as well as sst(2)/sst(5) selectivity.