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

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

Yeon Sun Lee  1 , Michael Remesic  2 , Cyf Ramos-Colon  2 , Zhijun Wu  3 , Justin LaVigne  1 , Gabriella Molnar  1 , Dagmara Tymecka  4 , Aleksandra Misicka  4 , John M Streicher  1 , Victor J Hruby  2 , Frank Porreca  1
Affiliations

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

Yeon Sun Lee et al. Biomedicines. .

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, 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.

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

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of enkephalin-like tetrapeptide analogs.
Figure 2
Figure 2
[35S]GTPγS assays in hKOR-CHO cells. Agonist mode dose–response curves of 5 and U50,488 (left). Antagonist mode dose–response curves of 5 and naloxone (right). Data points represent mean ± SEM of the percent of U50,488 stimulation. From n = 3 independent experiments for both modes. Three-variable non-linear regression curves fit by GraphPad Prism.
Figure 3
Figure 3
The structure of 6 (a) and alignment of the backbones of 6 along the kappa-specific area (light green) of the MOR agonist template (b).
Figure 4
Figure 4
Docking of 6 as aligned with the template (light green) onto the binding pocket of a KOR-JDTic complex (4djh).
Figure 5
Figure 5
Structural correlation between 6 (LYS744) and Chang1996-2. The structure of Chang1996-2 (a) and co-alignment of Chang1996-2 (grey) and 6 (light green) with the template (b).
Figure 6
Figure 6
Stabilities of 5 and 6 in human plasma at 37 °C. (a) HPLC profile of 5, EM-1, and Z-Lys-OH (internal standard); (b) after 1 h incubation at 37 °C. Gradient: 3–75% of B solution (0.05% HCOOH in acetonitrile) in A solution (0.05% HCOOH in water) within 48 min; (c) overall long-term stabilities of 5 in 50% human plasma; and (d) 6 in 95% human plasma.
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References

    1. Anand J.P., Montgomery D. Multifunctional opioid ligands. Handb. Exp. Pharmacol. 2018;247:21–51. - PubMed
    1. Morphy R., Kay C., Rankovic Z. From magic bullets to designed multiple ligands. Drug Discov. Today. 2004;9:641–651. doi: 10.1016/S1359-6446(04)03163-0. - DOI - PubMed
    1. Morphy R., Rankovic Z. Designing multiple ligands-medicinal chemistry strategies and challenges. Curr. Pharm. Des. 2009;15:587–600. doi: 10.2174/138161209787315594. - DOI - PubMed
    1. Dietis N., Guerrini R., Calo G., Salvadori S., Rowbotham D.J., Lambert D.G. Simultaneous targeting of multiple opioid receptors: A strategy to improve side-effect profile. Br. J. Anaesth. 2009;103:38–49. doi: 10.1093/bja/aep129. - DOI - PubMed
    1. Balboni G., Onnis V., Congiu C., Zotti M., Sasaki Y., Ambo A., Bryant S.D., Jinsmaa Y., Lazarus L.H., Lazzari I., et al. Further studies on the effect of lysine at the C-terminus of the Dmt-Tic opioid pharmacophore. Bioorg. Med. Chem. 2007;15:3143–3151. doi: 10.1016/j.bmc.2007.02.039. - DOI - PMC - PubMed

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