Analgesic Activity Of Intrathecl Administration Endomorphin Analogs With C-Terminal Esterified Modification

Endorphin-2(EM-2)is a highly selective and affinity receptor agonist for μ-opioid receptors.It has strong analgesic activity and low adverse reactions to neuropathic pain,but it is a natural peptide by itself.The inherent shortcomings of the drug,as well as some side effects such as respiratory depression,cardiovascular effects,constipation,etc.have not been put into clinical use as analgesic drugs.Aiming at the special structure of EM-2’s own main chain and aromatic ring side chain,this thesis explores the C-terminus of EM-2 to undergo methyl,ethyl and tert-butyl esterification to modify analogs 1-3 at the level of mouse spinal cord.The analgesic activity,mechanism of action and tolerability of EM,and the use of SNI model to further study the anti-neuropathic effects of EM-2 and analogues 1-3,to reserve suitable conditions for the clinical application of endomorphin.After intrathecal injection of the peptide drug under study,use the paw contraction threshold value produced by the mouse radiant heat stimulation test to calculate the maximum analgesic effect percentage(%MPE)and the drug dose required for 50% of the maximum analgesic effect(ED50 value)Determine the analgesic activity of the drug;co-administer five specific opioid receptor antagonists and peptide drugs to evaluate the analgesic mechanism of peptide drugs after esterification;draw tolerance curves through acute tolerance experiments And calculate the tolerance coefficient to determine the drug tolerance of EM-2 and its analogs 1-3;finally establish the SNI model using Von Frey filaments to determine the mechanical pain threshold of mice,and determine the resistance of peptide drugs in the spinal cord after esterification.Whether the opioid analgesic mechanism of neuralgia has changed.Radiation experiment results show that esterification modification improves the analgesic activity of EM-2 at the level of mouse spinal cord.The C-terminal analogs 1and 3 after esterification with methyl and tert-butyl are significantly better than EM-2.After co-administration of peptide drugs and antagonists,esterification modification changes the opioid mechanism of EM-2 analgesia.Both the parent peptide and analogue1 produce analgesic effects through μ1-and μ2-opioid receptors,similar Substance 2produces analgesic effects through μ2-opioid receptors,and analog 3 produces anti-noxious effects through μ2-and δ-opioid receptors.In the drug tolerance experiment,EM-2 and its analogs all produced drug tolerance.Esterification modification reduced the drug tolerance of EM-2,and analog 3 had the most significant improvement in tolerance.In the SNI model experiment,the esterification modification improved the analgesic effect and duration of EM-2 against neuralgia at the spinal cord level,and correspondingly changed the specific opioid receptor when the drug exerted an analgesic effect.The experimental results were normal.Mice were subjected to the same radiant heat stimulation,which further enriched the experimental data of the anti-injury effect of EM-2 and its analogues 1-3,and further pave the way for the use of endomorphin as a clinical drug.