Tallon M, Ron D, Halle D, Amodeo P, Saviano G, Temussi P A, Selinger Z, Naider F, Chorev M
Department of Chemistry, College of Staten Island, CUNY.
Biopolymers. 1993 Jun;33(6):915-26. doi: 10.1002/bip.360330607.
A highly potent and selective agonist to the tachykinin NK-3 receptor, [pGlu6,N-MePhe8,Aib9] substance P (6-11) (I), was synthesized via the solid phase method. The ED50 of I was 4 nM in the guinea pig ileum in the absence of atropine (NK-1+NK-3 receptors) and this agonist was 5000-fold less potent in the presence of atropine (NK-1 receptor). The analogue was virtually inactive in the rat vas deferens (NK-2 receptor). A detailed analysis of the solution conformation of this analogue in DMSO-d6 and in a DMSO-d6/H2O cryomixture was carried out by a combination of 1H-nmr 2D techniques (DQF-COSY, TOCSY, NOESY and ROESY) and model building based on empirical energy calculations. Peptide I exists as a mixture of isomers containing cis and trans Phe-N-MePhe peptide bonds. The main isomer, containing a cis Phe-N-MePhe peptide bond, shows a preferred folded conformation characterized by a type VI beta-turn with Phe and N-MePhe in the i + 1 and i + 2 positions. The turn is followed by a helical segment extending to the C-terminal. This conformation is compared to previously reported conformations of other selective tachykinin agonists and may be a promising lead for the design of novel NK-3 agonists with additional conformational constraints.
通过固相法合成了一种高效且选择性的速激肽NK-3受体激动剂，即[pGlu6，N-MePhe8，Aib9]P物质（6-11）（I）。在无阿托品（NK-1+NK-3受体）的情况下，I在豚鼠回肠中的ED50为4 nM，而在有阿托品（NK-1受体）存在时，该激动剂的效力低5000倍。该类似物在大鼠输精管（NK-2受体）中几乎无活性。通过1H-nmr二维技术（DQF-COSY、TOCSY、NOESY和ROESY）与基于经验能量计算的模型构建相结合，对该类似物在DMSO-d6和DMSO-d6/H2O冷冻混合物中的溶液构象进行了详细分析。肽I以含有顺式和反式Phe-N-MePhe肽键的异构体混合物形式存在。主要异构体含有顺式Phe-N-MePhe肽键，呈现出一种优选的折叠构象，其特征为在i + 1和i + 2位置含有Phe和N-MePhe的VI型β-转角。该转角之后是延伸至C端的螺旋段。将此构象与先前报道的其他选择性速激肽激动剂的构象进行了比较，它可能是设计具有额外构象限制的新型NK-3激动剂的一个有前景的先导物。
