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J Med Chem. 2013 Apr 11;56(7):3102-14. doi: 10.1021/jm400195y. Epub 2013 Mar 28.

Design, synthesis, and pharmacological characterization of novel endomorphin-1 analogues as extremely potent μ-opioid agonists.

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Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, and Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, PR China.


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 Dmt(1), (R/S)-βPro(2), and (ph)Map(4)/(2-furyl)Map(4). 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, Dmt(1)-(R)-βPro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) 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.

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