Design And Synthesis Of Bis-2,6-Dimethyl Tyrosine Compounds

In 1997,Zadina isolated two tetrapeptides,endomorphin-1(EM-1,Tyr-Pro-Trp-Phe-NH2)and endomorphin-2(EM-2,Tyr-Pro-Phe-Phe-NH2),from bovine frontal cortex,these two opioid peptides show high affinity and remarkable selective for μopioid receptor.They were reported to be the endogenous ligands to μ opioid receptors.Endomorphins can produce equivalent analgesia with morphine even in low concentrations,and have less undesirable side effects due to their characteristics of endogenous.The position 1 of opioid peptides is tyrosine,and links with the amino acids of position 3 or position 4 based on proline(endomorphin)or glycine(enkephalin),so the opioid peptides have the elementary structure of Tyr-spacer-Xaa.But peptides readily undergo metabolic degradation by peptidases and are difficult in transport through the blood-brain barrier(BBB).Therefore,designing and synthesis new and improved opioid peptides analogues by chemical modification is a effective way to develop compounds with less side effects and strong analgesic effect.It has been proved that the aromatic amino acids of position 1 and position 3 of opioid peptides play an important role on coupling with the opioid receptors.Our previous studies have shown that introduction of 2,6-dimethyl tyrosine(Dmt)to position 1 of opioid peptides could enhance receptor affinity and bioactivity.So,we used 1,4-piperazinediethanamine,1,4-piperazinedipropylanamine,1,4-piperazinedi-butylamine,p-xylylenediamine,m-xylylenediamine,diethylenetriamine,trans-1,4-diaminocyclohexane,1 S,2S-diaminocyclohexane,1 R,2R-diaminocyclohexane to synthesis a series of Dmt-spacer-Dmt compounds,and we also investigated the binding activity and in vitro functional activity of some compounds.The results have shown that 1,4-bis[Dmt-NH-(CH2)2]piperazidine(Ljc-1)and 1,4-bis[Dmt-NH-(CH2)3]piperazidine(Ljc-2)reflected high selectivity and good agonist activity to μ receptor(Ljc-1:Kiμ=0.045 nM,Kiδ/Kiμ=28488,GPI IC50 = 32 nM;Ljc-2:Kiμ=0.028 nM,Kiδ/Kiμ= 35964,GPI IC50 = 20 nM).In comparison,bis-Dmt-xylylene amine compounds(Ljc-4,Ljc-5)have relatively weak selectivity and agonist activity to μreceptor.These results made a good base in developing small molecule analgesias.