Endomorphin-1 Analogues Physiological Activity Assay

Compared with the alkaloid analgesics, Endomorphin-1 have many defects as the clinical analgesic that it has relatively low receptor selectivity and highly degradation speed in vivo,at the same time,it is not easy through the cerebral cortex film barrier which cause the formation of acute tolerance, body-dependent, respiratory depression, and disrupt the normal gastrointestinal. We introduce the experiment combinate non-natural amino acid Map into the three and four of the EM-1, by replaceing the amino acid in EM-1 with Map amino acid which has different group, forming a series of EM-1 analogs:(2) H-Tyr-Pro-Trp-(Ph)Map-NH2; (3) H-Tyr-Pro-Trp-(2-Furan) Map-NH2; (4) H-Tyr-Pro-Trp-(3-Furan)Map-NH2; (5) H-Tyr-Trp-(Ph)Map-NH2; (6) H-Tyr-Trp-(p-F)Map-NH2 In vitro experiments of MVD experiment in mice and guinea pig GPI experiment prove the affinity and activity of these analogs. Compared with EM-1, most of these analogs have higher affinity and capacity to MOR receptor.Compared with the activity of these analogues, we elect EM-1 analogues 2,3,4 which have good affinity and activity in the Kunming mouse vitro colon experiments, measure disorder simplications of the mouse colon. By comparison with EM-1 and analogues we found that analogs of 2,3,4 can cause shrinkage of the colon, and have greater contraction amplitude than EM-1. Based on these results we select atropine and naloxone making further research of the mechanism of EMs in colon, and have greater contraction amplitude than EM-1. Based on these results we select atropine and naloxone making further research of the mechanism of EMs in colon. The results show that naloxone completely inhibited the colon contraction caused by drugs which atropine can not. EM-1 and its analogues are mediated through opioid receptor caused the contraction of the longitudinal muscle of the mouse colon.It is Obviously that by import non-natural amino Map into the 4 position of EM-1, the physiological activity of their analogs can be significantly improved. Changes in the structure of EM-1 successfully improve biological activity, and these analogs may have potential application as analgesic drugs?...