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Molecular Design of delta-Selective Morphine Dimer Based on Enkephalin Conformation

基于脑啡肽构象的δ选择性吗啡二聚体的分子设计

基本信息

批准号：
63571029
负责人：
ISHIDA Toshimasa
金额：
$ 1.28万
依托单位：
Osaka University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

项目摘要

1. Chemical Syntheses of a Series of Morphine DimersBased on the possible relationship between the molecular conformations of enkephalin and the binding to mu/delta-opioid receptor, an attempt io structurally convert the mu-selective morphine molecule toward delta-selectivity was carried out by a series of morphine dimerizations. A series of morphine dimers in which the nitrogen atoms of two morphine molecules are linked by the -(CH_2)_n- [n= 0 - 6] linkage were chemically synthesized, and their physicochemical properties were elucidated by the spectroscopic method such as ^1H-NMR.2. Pharmacological Measurements of a Series of Morphine DimersPharmacologic activities of a series of morphine dimers were evaluated for the inhibitory effect on contraction of mouse isolated vas deferens and for the binding assay in homogenates of rat brain. The morphine dimer of n=2 exhibited the agonist activity showing about 15 timer more delta-selectivity than the parent morphine molecule, while that of n=3 showed a noticeable antagonist activity for mu/delta-receptor. The dimers of n 4 showed no significant pharmacological activities. The preference of n=2 dimer toward delta-receptor binding and the pharmacological difference between dimers of n=2 and 3 is an important information for considering the substrate specificity of mu/delta-opioid receptor.3. Relationship between the Stable Conformations of Morphine Dimers of n=3 and 3 and the Binding to delta-opioid ReceptorThe energetically stable conformations of morphine dimers of n=2 and 3 were investigated by the quantum chemical MNDO method. As a result, it was suggested as the most stable con- formations the extended planar form for n=2 dimer in which two morphine chromophores are almost related to each other with a C2-symmetry and the folded form without showing C2-symm- etry for n=3 dimer. This result clearly shows the preference of extended C2-symmetric conformation of opioid for the binding with delta-receptor.

1.一系列吗啡二聚体的化学合成基于脑啡肽分子构象与μ/δ-阿片受体结合之间可能存在的关系，尝试通过一系列吗啡二聚化将μ-选择性吗啡分子结构转变为δ-选择性。化学合成了一系列吗啡二聚体，其中两个吗啡分子的氮原子通过-(CH_2)_n-[n=0-6]键连接，并通过^1H-NMR等波谱方法阐明了它们的理化性质。2．一系列吗啡二聚体的药理学测量评估了一系列吗啡二聚体的药理学活性，以评价其对小鼠离体输精管收缩的抑制作用以及在大鼠脑匀浆中的结合测定。 n=2的吗啡二聚体显示出比母体吗啡分子高约15倍的δ选择性的激动剂活性，而n=3的吗啡二聚体显示出对mu/δ受体的显着拮抗活性。 n 4 的二聚体没有表现出显着的药理活性。 n=2二聚体对δ-受体结合的偏好以及n=2和3二聚体之间的药理学差异是考虑mu/delta-阿片受体底物特异性的重要信息。 3． n=3和3的吗啡二聚体的稳定构象与δ-阿片受体结合的关系通过量子化学MNDO方法研究了n=2和3的吗啡二聚体的能量稳定构象。因此，n=2 二聚体的扩展平面形式被认为是最稳定的构象，其中两个吗啡发色团几乎以 C2 对称性彼此相关，而 n=3 二聚体的折叠形式则不显示 C2 对称性。该结果清楚地表明阿片类药物的扩展 C2 对称构象更倾向于与 δ 受体结合。