Design And Synthesis Of Endomorphin Analogs With Basic Side Chains

It has been reported that ?-receptor knockout mice do not produce morphine tolerance while preserving morphine analgesic activity.Selectively blocking delta-receptors with ?-receptor antagonists can significantly reduce morphine tolerance and physical dependence.Likewise,?-receptor antagonists also inhibit morphine-dependent production.Pharmacological test results show that an opioid ligand with mixed ?-receptor agonistic activity,?-receptor antagonistic activity has low tolerance,physical and psychiatric dependence.Dmt-Pro-Xaa-Phe-NH2((Dmt:2,6-dimethyl-L-tyrosine,Xaa:Dmp(2,6-dimet hyl-L-phenyl-alanine,Tmp(2,4,6-trimethyl-L-phenylalanine),Trp,etc))was obtain ed by introducing an aromatic amino acid at the 1,3-position of the endomorphin,which is a strong systemic agonist activity and ?-receptor antagonistic activity of opioid molecules.In order to develop a series of opioid molecules with enzymatic stability and capable of activating ?-receptor agonist activity and ?-receptor antagonistic activity through the blood-brain barrier,the structural characteristics of[Dmt1]DALDA were introduced into Dmt-P ro-Xaa-Phe-NH2 sequence.In particular,the amino or guanidino group are introduced on Pro2 of[Dmt1]EMs,and Phe4 is substituted with a basic amino acid to synthesize the endomorphin derivative Dmt-Xaa2-Xaa3-Xaa4-NH2,wherein Xaa2 is a 4-position amino group or guanidine group Substituted non-natural Pro,Xaa3 is an aromatic amino acid Phe,Tmp or Trp,and Xaa4 is a basic amino acid Arg or Lys.In this paper,seven proline derivatives containing base side chain groups,including N-Fmoc-4-(cis-Boc-NH)-Pro-OH(C-1),N-Fmoc-4-(cis-diBoc-guanidyl)Pro-OH(C-2)?N-Fmoc-4-(trans-Boc-NH)-Pro-OH(C-3),N-Fmoc-4-(trans-diBoc-guanidyl)-Pro-OH(C-4),N-Fmoc-4-(cis-Boc-aminoethyl)-Pro-OH(C-5),N-Fmoc-4-(cis-diBoc-guanidylethyl)-Pro-OH(C-6),N-Fmoc-4-(cis-Boc-aminopropyl)-Pro-OH(C-7).Six endomorphine analogs containing basic side chains were synthesized from synthetic proline derivatives.The pharmacological activity of the compound is underway.