The Research On The Pharmaco-Activity Effects Of Endomorphin-1 Analogs And The Cardiovascular Effects Of XPP-EM1

Endomorphin-1 and endomorphin-2 are endogenous opiod peptides which were discoverd by Zadina in 1997 with high affinity and selectivity to p.-opiod receptors. The study on their structure-function relationship and physico-chemical property are nearly fifteen years since then, and we conclude that the two tetrapeptide can mediate an array of physiological processes including several behavioral, emotion, cardiovascular,gastrointestinal systems, and respiratory. There are a good many researches indicated that the most important physiological activity is their analgesic effects on acut pain. Furthermore, endomorphins are lack some of the morphine's side-effects, so endomorphinl and 2 are being extensively investigated as potential analgesic agents. As we all know, a well drug is not only have good pharmacodynamic action, but also should be low effects on the other aspects. So we should raise the analgesic activity, as well as low their side-effects on cardiovascular and gastrointestinal. The anterior investigate indicated that EM-1 had a more favorable therapeutic profile than EM-2. Herein, we chose EM-1 as our research object. In my paper, we with D-Val, and then connected it with cyclohexylamine and S-α-PEA, we also replaced the Phe4 with D-Ala, and then connected it with But-NH2, and three analogues were obtained. First, we did the assay on the analgesic activity of EM-1 and its three analogues. Then their effects on the blood pressure and heart rate of the anesthetic rats were detected. At last, we also did the research of longitudinal muscle contractions induced by EM-land its analogues. Our findings indicated that: the analog 2 is most potential to exploitation, because it possesses the equivalency activity on analgesic effect, but has less side-effect on cardiovascular and gastrointestinal. The last two analogs have separated good quality and shortage, analog 1 has a better analgesic activity than parent but its side-effects is much less than parent, although stronger than analog 2. However, the modulation effects on cardiovascular and gastrointestinal are as strong as parent, but its analgesic activity is about 15% higher than parent.Another part of the job in my paper is about milk protein-derived bioactivity tripetides IPP(isoleucine-proline-proline) and VPP(valine-proline-proline) which were consided to have the blood pressure-lowering effects. We connected the tripeptides and EM-1 with Gly through soild-phase synthesis. And we got four analoges Ile-Pro-Pro-Gly-Tyr-Pro-Trp-Phe-NH2,Val-Pro-Pro-Gly-Tyr-Pro-Trp-Phe-NH2 and Leu-Pro-Pro-Gly-Tyr-Pro-Trp-Phe-NH2 and Val-Tyr-Gly-Tyr-Pro-Trp-Phe-NH2. we detected the blood pressure-lowing effects of them, and our findings indicated that no one among the four analogs can decrease the blood pressure and heart rate as strong as EM1, furthermore, their effects were much lower than EM-1.