Yamazaki T, Said-Nejad O E, Schiller P W, Goodman M
Department of Chemistry, University of California, San Diego, La Jolla 92093-0343.
Biopolymers. 1991 Jun;31(7):877-98. doi: 10.1002/bip.360310708.
In order to study structure-activity relationships of enkephalin-related analogues, we report the biological activity and conformational analysis of four 14-membered cyclic enkephalin analogues with beta-(1-naphthyl) alanine in place of phenylalanine at the fourth position, Tyr-c[D-A2bu-Gly-(L and D)-beta Nal(1)-(L and D)-Leu]. The L-beta Nal(1)-containing analogues display higher activity at both the mu and delta receptors than the corresponding analogues with the L-Phe residue. In contrast to the linear enkephalins, the cyclic analogues with the D-beta Nal(1) residue are also active at the mu receptor since the relative spatial arrangement of functional groups required for biological activity is achieved by the constrained nature of the cyclic molecules. A comparison of the findings from the conformational analysis and biological assays establishes that relatively extended structures, in which the two aromatic side chains are oriented in opposite directions with a approximately 14 A separation, is required for activity at the mu receptor. On the other hand, folded conformations with nearly parallel orientations and a close proximity (less than 10A) of the aromatic rings of the Tyr and beta Nal(1) residues are required for activity at the delta receptor. It should be noted that the overall structures and thus the biological profiles of the 14-membered cyclic enkephalin analogues are strongly dependent on the conformation of the second residue. The folded conformations with parallel orientation of the two aromatic side chains of Tyr-c[D-A2bu-Gly-L-beta Nal(1)-D-Leu] is stabilized by an interaction between the Tyr phenolic OH proton and beta Nal(1) C*O groups. This analogue, which shows the highest activity at both the mu and delta receptors among the four stereoisomers studied, displays an increase of the fraction of the side-chain chi 1 = t conformer for the beta Nal(1) residue. It is concluded that the incorporation of the D-Leu residue at the fifth position increases the relative fraction of the folded conformations with parallel orientation of the aromatic side chains, and hence enhances activity at the delta receptor as compared to the corresponding L-Leu containing analogue.
为了研究脑啡肽相关类似物的构效关系，我们报道了四种14元环脑啡肽类似物的生物活性和构象分析，这些类似物在第4位用β-(1-萘基)丙氨酸取代苯丙氨酸，即Tyr-c[D-A2bu-Gly-(L和D)-βNal(1)-(L和D)-Leu]。含L-βNal(1)的类似物在μ和δ受体上均比相应含L-Phe残基的类似物表现出更高的活性。与线性脑啡肽不同，含D-βNal(1)残基的环类似物在μ受体上也有活性，因为生物活性所需官能团的相对空间排列是由环分子的受限性质实现的。构象分析和生物学测定结果的比较表明，μ受体活性需要相对伸展的结构，其中两个芳香侧链以相反方向排列，间距约为14 Å。另一方面，δ受体活性需要Tyr和βNal(1)残基的芳香环几乎平行且紧密接近（小于10 Å）的折叠构象。应该注意的是，14元环脑啡肽类似物的整体结构以及因此的生物学特性强烈依赖于第二个残基的构象。Tyr-c[D-A2bu-Gly-L-βNal(1)-D-Leu]的两个芳香侧链平行取向的折叠构象通过Tyr酚羟基质子与βNal(1) C*O基团之间的相互作用得以稳定。在研究的四种立体异构体中，该类似物在μ和δ受体上均表现出最高活性，其βNal(1)残基的侧链χ1 = t构象体的比例增加。得出的结论是，在第5位引入D-Leu残基增加了芳香侧链平行取向的折叠构象的相对比例，因此与相应含L-Leu的类似物相比，增强了在δ受体上的活性。
