Synthesis And Biological Activity Of[Dmt~1]DALDA Analogues

Pain is a common and severely disabling state that affects millions of people worldwide.Pain could be experienced after nerve injury,inflammation or as part of diseases that affect nervous system.The?-opioid receptor?MOR?,a G-protein coupled receptor expressed in the central and peripheral nervous systems,is activated by opioid compounds such as morphine,codeine,pethidine,and so on.Activated MOR initiates signaling cascades which result in potent analgesia.Opioids have been used for centuries to provide effective pain relief and continue to be essential tools in modern clinical pain management.However,the clinicalutility of opioid drugs is limited by side-effects that include gastrointestinal complications,respiratory depression,tolerance and dependence with long-term use.These limitations have stimulated the search for more effective analgesics that possess fewer side effects,and do not lead to tolerance or dependence.Modern pharmacological studies have suggested that the opioid ligands with mixed?-agonist/?-antagonist exhibit lower analgesic tolerance and physical dependence.The structure-activity relationship of endomorphins?EMs?have shown that introduction of aromatic amino acids with alkyl substitutions to position 1 and position 3 of EMs obtains[Dmt¹,Xaa³]EM-2?Dmt-Pro-Xaa-Phe-NH₂?,which is an opioid peptide with?-receptor antagonist as well as?receptor agonist of EMs.However,with relatively rapid degradation and limitly delivery to the central nervous system?CNS?,it is unlikely that[Dmt¹,Xaa³]EM-2 could be used for the clinical treatment of pain.Therefore,in order to develop excellent analgesic opioid receptor with the mixed profile previously described as well as low addiction and tolerance,it is necessary to be explored in depth for the structure-activity relationship studies of these complouds.Hope to improve the resistance to enzymatic degradation and the ability to cross the blood-brain barrier?BBB?while preserving the mixed profile of original ligands.The dermorphin-derived tetrapeptide[Dmt¹]DALDA?Dmt-D-Arg-Phe-Lys-NH₂?is a highly potent and extraordinary selectivity?-opioid receptor agonist.It carries a net positive charge of 3+at physiological pH.Despite its polar nature,[Dmt¹]DALDA is readily distributed to the CNS and produces long-lasting analgesic effects after systemic administration.[Dmt¹]DALDA also has a strong antinociceptive effect and a high metabolic stability.The only drawback of this compound is that it produced quite profound tolerance after chronic i.th.Administration.The high metabolic stability and the ability to cross the BBB of[Dmt¹]DALDA happens to meet the demand of[Dmt¹,Xaa³]EM-2 with the mixed profile.Therefore,according to the structural features of the two,seven Dmt-D-Arg-Xaa-Lys-NH₂compounds were designed and synthesized by using the Fmoc strategy of solid phase peptide synthesis,in which Xaa is a natural or unnatural aromatic amino acid,such as Dmp,Tmp,L-2-Nal,L-2-Nal,Trp,Imp,Emp and so on.The structures of the products were characterized by ¹H NMR,¹³C NMR and MS.Activity tests revealed that synthesized[Dmt¹]DALDA analogues show strong?/?opioid receptor agonist activity.Among them,CJJ 1,CJJ 2b,CJJ 4 and CJJ 6were shows a more balanced?/?opioid receptor agonist activity.Studies have shown that the compounds with the above properties have low tolerance and dependence.Therefore,these compounds are worthy of pharmacological studies in depth.