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

点击翻译按钮获取中文摘要

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.