Multifunctional enkephalin analogs with a new biological profile: Mor/dor agonism and kor antagonism

Yeon Sun Lee, Michael Remesic, Cyf Ramos-Colon, Zhijun Wu, Justin Lavigne, Gabriella Molnar, Dagmara Tymecka, Aleksandra Misicka, John M. Streicher, Victor J Hruby, Frank Porreca

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


In our previous studies, we developed a series of mixed MOR/DOR agonists that are enkephalin-like tetrapeptide analogs with an N-phenyl-N-piperidin-4-ylpropionamide (Ppp) moiety at the C-terminus. Further SAR study on the analogs, initiated by the findings from off-target screening, resulted in the discovery of LYS744 (6, Dmt-DNle-Gly-Phe(p-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPS assay: IC50 = 52 nM, Imax = 122% cf. IC50 = 59 nM, Imax = 100% for naloxone) with nanomolar range of binding affinity (Ki = 1.3 nM cf.Ki = 2.4 nM for salvinorin A). Based on its unique biological profile, 6 is considered to possess high therapeutic potential for the treatment of chronic pain by modulating pathological KOR activation while retaining analgesic efficacy attributed to its MOR/DOR agonist activity.

Original languageEnglish (US)
Article number625
Issue number6
StatePublished - Jun 2021


  • Analgesic effects
  • Kappa receptor antagonists
  • Multifunctional activity
  • Opioid receptors
  • Peptidomimetics
  • Plasma stability
  • Template-based alignment modeling

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology


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