Analgesic Activity Of Endomorphin Analogues With C-terminal Hydrazide Modification

Endomorphin is an endogenous ligand for the?-opioid receptor with high receptor affinity and selectivity.EMs have a strong analgesic effect in the central and peripheral nervous systems with minor side effects,but still have many shortcomings that limit their clinical application.Therefore,many scholars are committed to the modification of the structure of endomorphin,which increases the analgesic activity and reduces the side effects of opioids.This study was to investigate the analgesic activity,mechanism and tolerance of endomorphin C-terminal hydrazide-modified analogues at the spinal level of mice,and further use the SNI model.In the mouse radiation paw experiment,calculate MPE%and ED₅₀ values,draw dose-response curve to compare the analgesic effects of EMs and analogs.Opioid recep-tor antagonists were then used to determine whether the hydrazide modification altered the opioid mechanism of action of EMs.Then determine drug tolerance,and an acute tolerance curve was drawn and the tolerance coefficient was determined.This study also used the nerve injury model to study the anti-neuropathic effects of EMs and analogs after intrathecal administration,established a mouse SNI model and determined the pain threshold,and used mechanical stimulation to determine the analgesia of peptide drugs on the spinal cord level of mice active.The results indicated that EM-1-NHNH₂ showed the highest analgesic activity after intrathecal administration,mean the C-terminal hydrazide modification was significant.It is known by the action of antagonists that both EM-1 and EM-1-NHNH₂are mediated by the?2 opioid receptor;EM-2 may produce analgesic effects through the?1-,?2-and?-opioid receptor subtypes.Whereas the analog EM-2-NHNH₂ is administered only by the?2-opioid receptor.Acute tolerance experiments showed that EMs and analogs were resistant,and EM-2-NHNH₂ produced the least tolerance at the spinal level,indicating that C-terminal hydrazide modification reduced the drug resistance of EMs to some extent.In the mouse SNI model,the analog EM-1-NHNH₂produced the strongest analgesic effect even higher than the maternal EM-1,and the anti-neuropathic effect of EM-2-NHNH₂ and EM-2 on the spinal cord level was similar.This is consistent with our experimental results in normal mice.The results of this experiment will provide some experimental ideas for the synthesis of novel endomorphin analogues.