本文研究內嗎啡肽-二型分子(H-Tyr-Pro-Phe-Phe-NH2，EM-2)及其C端官能基經聯胺(CONHNH2)與甲基脂(COOMe)修飾後的類似物分子，並觀察這三種分子間(總稱：EM-2s)的結構-活性關係。這些C端修飾物在受體結合試驗中已被證實對μ型阿片受體除了能保留相同的親和力外，更增加了對受體的選擇性。本文主要的目的是藉由芳香環的側鏈構形來討論這些修飾後的EM-2分子是如何更具有活性。首先，將EM-2s分子置於真空環境中並利用半經驗的奧斯汀模型計算來進行局部構形收尋，再針對Tyr1-Pro2胺基酸鍵結部份獲得含順式/逆式兩種組態的低能量構形，這些構形將當作分子動力學模擬的初始結構，在水溶液的環境中進行20奈秒的模擬。現階段的研究成果，我們發現C端修飾對EM-2分子的影響主要在芳香環的側鏈構形(χ1)，但在背骨的扭轉角方面則無太大變化。針對側鏈構形部分，我們利用前人所提出的一些活性側鏈構形資訊來描述EM-2s分子對μ型阿片受體其選擇性的關係。從單一側鏈構形的分析，利用含活性側鏈構形準則來描述μ型阿片受體似乎有點不明確，因此我們更進一步利用活性側鏈構形組合分析來描述順式與逆式組態的EM-2s分子的結構-活性關係。關於這些活性側鏈構形組合，我們以[Tyr1— Phe3—Phe4]的型態來表示EM-2分子活性側鏈構形的組合，包含：[trans－trans－g(-)]和[g(-)－trans－g(-)]兩種組合。其結果顯示逆式組態的EM-2s分子比順式組態的EM-2s分子可能還要適合與μ型阿片受體產生鍵結，且C端官能基經修飾過後將明顯增加活性的側鏈構形組合。也就是：類似物2＞類似物3＞內嗎啡肽-二型分子。因此，我們推論當EM-2s分子呈現逆式組態時對μ型阿片受體將可能有較高的親合性或選擇性。

The structure-activity relationships of the endomorphin-2 (H-Tyr1-Pro2-Phe3-Phe4-NH2, EM-2) and two modified analogues (EM-2s) with hydrazine group (-CONHNH2, analogue 2) and methyl ester (-COOMe, analogue 3) at the C-terminus have been investigated in this study. These C-terminal modified analogues had been proven in receptor binding assays that conserved the binding affinities and had higher selectivity to μ-opioid receptor (MOR). The main purpose of this study is focused on explaining how the EM-2 with the C-terminal modifications are more bioactive by analyzing the conformation of aromatic side-chain. The local conformational search of EM-2s were performed by Semi-Empirical Austin Model 1 calculation in vacuo, and containing the cis/trans isomers with the Tyr1-Pro2 peptide bond were obtained in a low-energy conformers, which were selected as the initial structures for molecular dynamic simulations in aqueous solution with a timecourse of 20 ns. In current study, we found the effect of the C-terminal modifications was mainly influenced on the rotamer (χ1) of the aromatics, but slightly affect on the dihedral angles of backbone. For side-chain rotamer analysis, we utilized the bioactive χ1 conformations that were mentioned in previous studies to describe the selectivity between the EM-2s and MOR. From the analysis of individual side-chain conformation, it seemed a criterion to determine the conformational bioactivity toward to MOR is clearly insufficient. Thus, we have further employed the bioactive rotamer- combination approach to examine the characteristic of SAR for cis-/trans-EM-2s. Those bioactive conformations can generally be classified into two conformer-combinations expressed in [Tyr1－Phe3－Phe4] format: [trans－trans－g(-)] and [g(-)－trans－g(-)]. The results show that the trans-EM-2s are more suitable than cis-EM-2s for MOR binding, and the modifications at the C-terminus functional group would increase the bioactive rotamer-combination conformations. i.e. analogue 2 (33.92%) > analogue 3 (26.67%) > EM-2 (21.57%) for trans isomers. Thus, we demonstrated that the trans-EM-2s possess higher binding affinity and selectivity to MOR.

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