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

doi:10.3390/biomedicines9060625

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

Biomedicines. 2021 May 31;9(6):625. doi: 10.3390/biomedicines9060625.

Authors

Affiliations

¹ Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA.
² Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
³ ABC Resource, Plainsboro, NJ 08536, USA.
⁴ Faculty of Chemistry, University of Warsaw, Pasteura, PL-02-093 Warsaw, Poland.

Abstract

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 (GTPγS assay: IC₅₀ = 52 nM, I_max = 122% cf. IC₅₀ = 59 nM, I_max = 100% for naloxone) with nanomolar range of binding affinity (K_i = 1.3 nM cf. K_i = 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.

Keywords: analgesic effects; kappa receptor antagonists; multifunctional activity; opioid receptors; peptidomimetics; plasma stability; template-based alignment modeling.

Abstract

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