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Recently we reported the synthesis and structure-activity study of endomorphin-1(EM-1)analogues containing novel,unnatural α-methylene-β-aminopropanoic acids(Map).In the present study,we describe new EM-1 analogues containing Dmt1,(R/S)-βPro2,and(ph)Map4/(2-furyl)Map4.All of the analogues showed a high affinity for the μ-opioid receptor(MOR)and increased stability in mouse brain homogenates.Of the new compounds,Dmt1-(R)-βPro2-Trp3-(2-furyl)Map4 displayed the highest affinity toward MOR,in the picomolar range(Ki μ = 3.72 pM).Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency,in the subpicomolar range(EC50 = 0.0421 pM,Emax = 99.5%).This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test,which indicates that this analogue was able to cross the blood?brain barrier.