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By NMR spectroscopy and molecular modeling having antagonist activity ENDOMORPHIN -2 analogues conformational analysis

Author: YaoJinLong
Tutor: WangRui
School: Lanzhou University
Course: Biochemistry and Molecular Biology
Keywords: Endomorphins -2 μ- opioid antagonist NMR spectrum Conformational analysis Molecular modeling
CLC: R96
Type: Master's thesis
Year: 2009
Downloads: 89
Quote: 0
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Opioid system is involved in many pharmacological effects through endogenous opioid ligand binding and activation of opioid receptors resulting membrane connected. It has been found three types of opioid receptors, μ, δ and κ belong to the G protein-coupled receptor family. 1997, endomorphins -1 (H-Tyr-ProTrp-Phe-NH 2 ) and endomorphins -2 (H-Tyr-Pro-Phe-Phe-NH 2 < / sub>) be separated and purified from bovine brain, which is a μ-opioid receptor with high affinity and selectivity of the endogenous opioid peptides. Since μ-opioid receptor-mediated analgesia produced many morphine and morphine Endomorphins relative to the induced analgesia while not produce some side effects, so they are considered to be the development of new analgesic model peptides. Recently, by endomorphins -2 3 or 4 non-natural substitute 3 - (1/2- naphthyl) alanine ( L or D configuration), researchers in addition to obtain μ-opioid receptor agonist, also found two μ-opioid receptor antagonist. As we all know, opioid antagonist opioid research and drug addiction treatment, have played an irreplaceable role. However, at present the resulting peptides derived μ-opioid receptor antagonist, little. But there is no structure on such research antagonists, so by measuring NMR spectrum of the spatial conformation of these peptides, it will find the related structural elements antagonistic great help. In this study, we have these Endomorphins -2 analogues, through 1D and 2D 1 H NMR spectroscopy, molecular modeling, for their conformation analyzed, including the determination of cis / trans isomers The ratio of main chain and side chain dihedral angles, aromatic ring aromatic interactions, and the N-terminal N atom and the C-terminal Cα Cα spacing so. We found that endomorphin-2 4-substituted analogs, with the proportion of cis and trans isomers of the parent increased to 1:1 1:2. Moreover, according to the atomic distance N (1) -αC (4) result, two analogs having antagonistic activity ([ D - 1-Nal 4 ] EM2 and [ D -2-Nal 4 ] EM2), they are in the cis conformation in all analogue is most curved, and their trans conformation is the most stretched. In addition, through structural superposition found that all analogues cis conformation, only these two peptides with endomorphins -2 most similar structure, which we propose that the cis-bent conformation, it may be caused by two an analogue μ-antagonist activity with structural factors. Considering the NMR structure reflects a rapid conformational transition average not fully reflect the diversity of conformation, therefore, based on the NMR structure, and by molecular dynamics calculation of these structural analysis a step further.

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