The Study On Blood-brain Barrier Permeability Of Endomorphin-1 Using Cell-penetrating Strategy

The endomorphins(EMs)not only possess highly ?-opioid receptor affinity and selectivity,but also have outstanding analgesic effect on a variety of pain.However,as the peptide compounds,EMs has poor permeability of acrossing BBB.The intra-cerebroventricular injection results analgesic activity,whereas peripheral administration has limited effect.Cell-penetrating peptides are reported that can improve the brain uptake of drugs without damaging the integrity of BBB.In this study,endomorphin-1 was modified aiming at the enhancement of brain target delivery,using Cell-penetrating Strategy.EM1-Cys,HDADC-Cys and the cell-penetrating peptide SynB3 has been synthesized using solid-phase peptide syntesis.Crosslinker SPDP(N-Succinimidyl 3-(2-Pyridyldithio)-Propionate)has also been synthesized.Disufide has been facilitated to construct link between cell-penetrating peptide and EMs using SPDP.The pharmacological activity of analogues had been evaluated using mouse tail-flick test;the degradation rate of the peptide had been determined with RP-HPLC in order to examine the stability.The results demonstrated that peripheral administration of endomorphin derivatives possesses excellent analgesic activity;the disulfide in derivatives could rapidly degradate in the 37? brain plasma membrane incubation.It has been concluded that endomorphin derivatives can cross the blood-brain barrier in the role of cell-penetrating peptide.After entering the central nervous system,the disulfide bond could be rapidly eliminated,and then EMI analogues was released which combine with the?-opioid receptor so that induce analgesic effect.This study provided a new idea for brain target delivery of the central nervous system drugs.