鎮痛薬をめざしたダイノルフィンＡ誘導体の合成研究 [in Japanese] Design and synthesis of metabolically stable analogue of dynorphin-A. [in Japanese]
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There are two difficulties for peripherally administered peptides to display their activities in central nervous system (CNS). First, a small amount of peptide is easily inactivated by peptidases present in blood and peripheral tissues. Second, peptides that do reach CNS are also digested by proteases in CNS before binding to their specific receptors. Dynorphin-A was degraded by incubation with mouse serum and mouse brain homogenates at 37°C in the presence or absence of protease inhibitors which were used to prevent secondary degradation of fragments. With the basic knowledge of the enzyme-susceptible sites of dynorphin-A, structure-activity relationships were studied so that we were able to reach the metabolically stable analogue (<I>E</I>-2078) whose structure is (<I>N</I>-MeTyr<SUP>1</SUP>, <I>N</I>-MeArg<SUP>7</SUP>, D-Leu<SUP>8</SUP>) dynorphin-A (1-8) ethylamide. This compound showed stronger analgesic activity than morphine by peripheral administration and was successfully massproduced by the development of the new deblocking method.
- Journal of Synthetic Organic Chemistry, Japan
Journal of Synthetic Organic Chemistry, Japan 49(1), 16-25, 1991
The Society of Synthetic Organic Chemistry, Japan