Cyclic beta-casomorphin analogues with mixed mu agonist/delta antagonist properties: synthesis, pharmacological characterization, and conformational aspects.
Cyclic beta-casomorphin analogues with mixed mu agonist/delta antagonist properties: synthesis, pharmacological characterization, and conformational aspects.
复制标题
具有混合 mu 激动剂/δ 拮抗剂特性的环状 β-酪啡肽类似物：合成、药理学表征和构象方面。
DOI：
10.1021/jm00034a011
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发表时间：
1994
影响因子：
7.3
通讯作者：
Schiller,PW
中科院分区：
文献类型：
--
作者：
Schmidt,R;Vogel,D;Mrestani-Klaus,C;Brandt,W;Neubert,K;Chung,NN;Lemieux,C;Schiller,PW
用常规溶液合成法合成了强效和中等选择性的阿片受体选择性环状d-酪蛋白-5衍生物H-Tyr-c[-D-Orn-Phe-D-Pro-Gly-](2)。用2-萘丙氨酸(2-NAL)取代Phe3残基，得到对µ和阿片受体均有高亲和力的多肽(4)。该化合物在以受体为代表的豚鼠回肠(GPI)实验中是一种激动剂，而在以受体为代表的小鼠输精管(MVD)实验中则是一种中等强度的拮抗剂。因此，它是第一个已知的具有混合µ激动剂/拮抗剂性质的环状阿片肽类似物。有趣的是，化合物4中的2-Nal3被1-萘丙氨酸(1-NAL)取代，得到一个类似物(5)，显示出对µ受体的高亲和力，并在由µ和受体介导的MVD分析中完全发挥激动剂作用。用色氨酸取代2(化合物8)中的Phe3在两种受体上都有很好的耐受性，并在GPI和MVD测定中都产生了具有激动剂活性的类似物。通过用D-赖氨酸(化合物6)或D-2，4-二氨基丁酸(化合物7)取代D-Orn2来实现4中肽大小的变化。类似物6也是一种混合的µ激动剂/拮抗剂，其效价略低于4，而化合物7显示了µ激动剂和部分激动剂的特性。通过删除Gly5残基进一步减小多肽环的大小，产生在两种生物检测中都是完全激动剂的化合物(9)。用核磁共振波谱和分子力学方法对类似物2、4和5进行了构象分析，结果表明，母体化合物2和含2-NaL的多肽4的整体构象相似，而多肽5中1-NaL的侧链取向不同。这些结果表明，类似物4的拮抗特性可能不是由于其整体构象与激动剂2的不同，而可能是2-萘基结构本身的直接作用，阻止了受体激活所需的肽的正确排列。开发对三个主要阿片受体类别(µ，，)具有高度特异性的有效的阿片激动剂和激动剂仍然是阿片药理学关注的主要问题。此外，目前特别关注寻找在一种受体类型上产生激动剂效应而在另一类受体上起拮抗剂作用的混合阿片类激动剂/拮抗剂。最近，研究表明，用非肽类拮抗剂纳曲哚预处理小鼠可防止吗啡耐受和依赖的形成。2这一有趣的观察表明，开发一种具有µ激动剂/拮抗剂混合特性的单一化合物可能具有相当大的治疗潜力。已知的第一个混合µ激动剂/拮抗剂的例子是最近报道的阿片四肽类似物H-Tyr-Tic-Phe-Phe-NH2(TIPP-NH2)。1‘3
Analogues of the potent and moderately µ-opioid-receptor-selective cyclic d-casomorphin-5 derivative H-Tyr-c [-D-Orn-Phe-D-Pro-Gly-](2) were prepared by conventional solution synthesis. Replace-ment of the Phe3 residue by 2-naphthylalanine (2-Nal) led to a peptide (4) with high affinity for both µ and opioid receptors. This compound turned out to be an agonist in the µ-receptor-representative guinea pig ileum (GPI) assay but a moderately potent antagonist against various agonists in the-receptor-representative mouse vas deferens (MVD) assay. It thus represents the first known cyclic opioid peptide analogue with mixed µ agonist/antagonist properties. Interestingly, replacement of 2-Nal3 in compound 4 with 1-naphthylalanine (1-Nal) resulted in an analogue (5) showing high affinity for µ receptors and a full agonist effect in the MVD assay that was mediated by both µ and receptors. Substitution of Trp for Phe3 in 2 (compound 8) was well tolerated at both receptors and led to an analogue with agonist activity in boththe GPI and MVD assays. Variation of the peptidering size in 4 was achieved bysubstitution of D-Orn2 with D-Lys (compound 6) or D-2, 4-diaminobutyric acid (compound 7). Analogue 6 was also a mixed µ agonist/antagonist with somewhat lower potencythan 4, whereas compound 7 displayed µ agonist and partial agonist properties. Further reduction of the peptide ring size, as achieved by deletion of the Gly5 residue, produced a compound (9) which was a full agonist in both bioassays. Conformational analysis of analogues 2, 4, and 5 by NMR spectroscopy and molecular mechanics studies suggested that the overall conformation of parent compound 2 and the 2-Nal-containing peptide 4 was similar, while the side-chain orientation of 1-Nal in peptide 5 was different. These results suggest that the antagonist properties of analogue 4 may not be due to a difference in its overall conformation as compared to the agonist 2 but may be a direct effect of the 2-naphthyl moiety per se preventing proper alignment of the peptide for receptor activation.The development of potent opioid agonists and an-tagonists with high specificity for each of the threemajor opioid receptor classes (µ,,) continues to be of major concern in opioidpharmacology. Furthermore, special attention is presently focused on the search for mixed opioid agonist/antagonists that produce an agonist effect at one receptor type and act as an antagonist at another receptor class. Recently, it was demonstrated that pre-treatment of mice with the nonpeptide antagonist naltrindole prevented the development of morphine tolerance and dependence. 2 This interestingobservation suggested that the developmentof a single compound with mixed µ agonist/antagonist properties may have con-siderable therapeutic potential. The first known example of a mixed µ agonist/antagonist is the recently reported opioid tetrapeptide analogue H-Tyr-Tic-Phe-Phe-NH2 (TIPP-NH2). 1'3