Sleszyńska Małgorzata, Kwiatkowska Anna, Sobolewski Dariusz, Wierzba Tomasz H, Katarzyńska Joanna, Zabrocki Janusz, Borovickova Lenka, Slaninová Jirina, Prahl Adam
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland.
Acta Biochim Pol. 2009;56(4):641-8. Epub 2009 Dec 7.
In the present study we describe the synthesis and some pharmacological properties of eight new analogues of bradykinin (BK). Two peptides were designed by substitution of position 7 or 8 of the known [D-Arg(0),Hyp(3),Thi(5,8),D-Phe(7)]BK antagonist (Stewart's antagonist) with L-pipecolic acid (L-Pip). The next two analogues were obtained by replacement of the d-Phe residue in position 7 of the Stewart's peptide with L-beta(2)-isoproline (L-beta(2)-iPro) or L-beta(3)-homoproline (L-beta(3)-hPro). The four analogues mentioned above were also prepared in N-acylated form with 1-adamantaneacetic acid (Aaa). Biological activity of the compounds was assessed by isolated rat uterus and rat blood pressure tests. Our results showed that L-Pip in position 7 slightly increased antagonistic potency in the blood pressure test, but it turned the analogue into an agonist in the rat uterus test. Replacement of Thi by L-Pip in position 8 also enhanced antagonism in the rat pressure test but preserved the antagonism in the rat uterus test. L-beta(2)-iPro or L-beta(3)-hPro in position 7 decreased the potencies in both tests. We also demonstrated that acylation of the N-terminus did not increase, as was claimed previously, the antagonistic potencies of the resulting peptides. The results thus support the hypothesis about the existence of different types of BK receptors in the rat uterus and blood vessels. Our studies provide new information about the structure-activity relationship of BK antagonists which may help in designing more potent BK receptor blockers.
在本研究中，我们描述了八种缓激肽（BK）新类似物的合成及其一些药理学特性。通过用L-哌啶酸（L-Pip）取代已知的[D-精氨酸（0），Hyp（3），硫代（5,8），D-苯丙氨酸（7）]BK拮抗剂（Stewart拮抗剂）的第7或8位设计了两种肽。接下来的两种类似物是通过用L-β（2）-异脯氨酸（L-β（2）-iPro）或L-β（3）-高脯氨酸（L-β（3）-hPro）取代Stewart肽第7位的d-苯丙氨酸残基而获得的。上述四种类似物也制备成了1-金刚烷乙酸（Aaa）的N-酰化形式。通过离体大鼠子宫和大鼠血压试验评估了这些化合物的生物活性。我们的结果表明，第7位的L-Pip在血压试验中略微提高了拮抗效力，但在大鼠子宫试验中它使类似物变成了激动剂。第8位用L-Pip取代硫代也增强了大鼠血压试验中的拮抗作用，但在大鼠子宫试验中保留了拮抗作用。第7位的L-β（2）-iPro或L-β（3）-hPro在两种试验中都降低了效力。我们还证明，如先前所声称的那样，N端酰化并没有提高所得肽的拮抗效力。因此，这些结果支持了大鼠子宫和血管中存在不同类型BK受体的假设。我们的研究提供了关于BK拮抗剂构效关系的新信息，这可能有助于设计更有效的BK受体阻滞剂。
