The Study Of New Type Casomorphin On Its Design,Synthesis, Selection And Structure-activity

Opioid peptides (Sedative anesthesia peptide), which is regard as neuroactive substances, can influence central nervous system and peripheral organs by the functions of hormone and neurotransmitter. This neuroactive includes the endogenous opioid peptides and the exogenous ones. Human beings can format some endogenous under some special conditions. Exogenous opioid peptides could be gotten from the exogenous substance such as food. Milk is considered as an important source. Our experiment had already got a piece of casomorphin by enzymatic casein, which has opioid activity. This quence is NH₂-Tyr-Phe-Tyr-Pro-Glu-Leu-Phe-Arg-Gln-Phe-Tyr- Gln-Leu-Asp-Ala-OH, the molecular weight is 2252.48.The animal tests showed the casomorphin which was gotten from enzymolysis and the casomorphin got by our laboratory had similar effects of analgesic and fatigue. On this basis, the tests used the casomorphin sequence as parent sequence,6 kinds of new casomorphin were designed appropriately according to the principles of charge distribution and similar structure:(1) NH₂-Tyr-Phe-Trp-Pro-Glu-Leu-Phe-Arg-Gln-Phe-Tyr-Gln-Leu-Asp-Ala-OH;(2) NH₂-Tyr-Phe-Phe-Pro-Glu-Leu-Phe-Arg-Gln-Phe-Tyr-Gln-Leu-Asp-Ala-OH;(3) NH₂-Tyr-Gly-Tyr-Pro-Glu-Leu-Phe-Arg-Gln-Phe-Tyr-Gln-Leu-Asp-Ala-OH;(4) NH₂-Tyr-Phe-Tyr-Pro-Glu-Leu-Phe-Arg-Gln-Phe-Tyr-Gln-Leu-OH;(5) NH₂-Tyr-Phe-Tyr-Pro-Glu-Leu-Phe-Arg-Gln-Phe-OH;(6) NH₂-Tyr-Phe-Tyr-Pro-Glu-Leu-Phe-Arg-OH.The average yield of synthesis of the 6 kinds of new casomorphin is 56.86% by the method of solid phase peptide synthesis.In order to compare the biological activity of the 6 kinds of new type with casomorphin which are got through enzymolysis and synthesis, analgesic test and experimental peripheral analgesia had been done. The result showed that all of the 6 kinds of casomorphin had the effectiveness of analgesic and peripheral analgesia. The analgesia effectiveness of (1)-(4) were better than the previous peptides, but had less stability. However, the (5), (6) are worse than the previous peptides. Combining the two analgesia tests, the order of the 6 kinds of new type casomorphin active is: (4)> (3)> (2)> (1), (6)> (5).The spatial structure simulation and receptor simulation by syby6.92 can give some reasonable explanation for the results. The results of simulation showed: samples of (1), (2), (6) could bind selectively withμreceptor; samples of (3), (5) could bind selectively withκreceptor; sample (4) could bind selectively withδreceptor only. However, only the sample (3), (4) could bind themselves with the active cavity of selected receptor successful.The results were accordance with the animal tests.