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Papers of the Week

Papers: 29 May 2021 - 4 Jun 2021

Pharmacology/Drug Development

2021 May 31




Multifunctional Enkephalin Analogs with a New Biological Profile: MOR/DOR Agonism and KOR Antagonism.


Lee Y S, Remesic M, Ramos-Colon C, Wu Z, LaVigne J, Molnar G, Tymecka D, Misicka A, Streicher JM, Hruby VJ, Porreca F
Biomedicines. 2021 May 31; 9(6).
PMID: 34072734.


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 (, Dmt-DNle-Gly-Phe(-Cl)-Ppp), a multifunctional ligand with MOR/DOR agonist and KOR antagonist activity (GTPγS assay: IC = 52 nM, I = 122% cf. IC = 59 nM, I = 100% for naloxone) with nanomolar range of binding affinity ( = 1.3 nM cf. = 2.4 nM for salvinorin A). Based on its unique biological profile, 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.