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Article

Synthesis, Pharmacological Evaluation, and Computational Studies of Cyclic Opioid Peptidomimetics Containing β3-Lysine

1
Department of Biomolecular Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
2
Department of Neuropeptides, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland
3
TriMen Chemicals Ltd., 92-318 Lodz, Poland
4
Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Academic Editors: Mariana Spetea and Richard M. van Rijn
Molecules 2022, 27(1), 151; https://doi.org/10.3390/molecules27010151
Received: 13 November 2021 / Revised: 24 December 2021 / Accepted: 25 December 2021 / Published: 28 December 2021
Our formerly described pentapeptide opioid analog Tyr-c[D-Lys-Phe-Phe-Asp]NH2 (designated RP-170), showing high affinity for the mu (MOR) and kappa (KOR) opioid receptors, was much more stable than endomorphine-2 (EM-2) in the rat brain homogenate and displayed remarkable antinociceptive activity after central (intracerebroventricular) and peripheral (intravenous ) administration. In this report, we describe the further modification of this analog, which includes the incorporation of a β3-amino acid, (R)- and (S)-β3-Lys, instead of D-Lys in position 2. The influence of such replacement on the biological properties of the obtained analogs, Tyr-c[(R)-β3-Lys-Phe-Phe-Asp]NH2 (RP-171) and Tyr-c[(S)-β3-Lys-Phe-Phe-Asp]NH2, (RP-172), was investigated in vitro. Receptor radiolabeled displacement and functional calcium mobilization assays were performed to measure binding affinity and receptor activation of the new analogs. The obtained data revealed that only one of the diastereoisomeric peptides, RP-171, was able to selectively bind and activate MOR. Molecular modeling (docking and molecular dynamics (MD) simulations) suggests that both compounds should be accommodated in the MOR binding site. However, in the case of the inactive isomer RP-172, fewer hydrogen bonds, as well as instability of the canonical ionic interaction to Asp147, could explain its very low MOR affinity. View Full-Text
Keywords: opioid receptors; β-amino acids; peptide synthesis; receptor binding studies; functional assay opioid receptors; β-amino acids; peptide synthesis; receptor binding studies; functional assay
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MDPI and ACS Style

Wtorek, K.; Lipiński, P.F.J.; Adamska-Bartłomiejczyk, A.; Piekielna-Ciesielska, J.; Sukiennik, J.; Kluczyk, A.; Janecka, A. Synthesis, Pharmacological Evaluation, and Computational Studies of Cyclic Opioid Peptidomimetics Containing β3-Lysine. Molecules 2022, 27, 151. https://doi.org/10.3390/molecules27010151

AMA Style

Wtorek K, Lipiński PFJ, Adamska-Bartłomiejczyk A, Piekielna-Ciesielska J, Sukiennik J, Kluczyk A, Janecka A. Synthesis, Pharmacological Evaluation, and Computational Studies of Cyclic Opioid Peptidomimetics Containing β3-Lysine. Molecules. 2022; 27(1):151. https://doi.org/10.3390/molecules27010151

Chicago/Turabian Style

Wtorek, Karol, Piotr F.J. Lipiński, Anna Adamska-Bartłomiejczyk, Justyna Piekielna-Ciesielska, Jarosław Sukiennik, Alicja Kluczyk, and Anna Janecka. 2022. "Synthesis, Pharmacological Evaluation, and Computational Studies of Cyclic Opioid Peptidomimetics Containing β3-Lysine" Molecules 27, no. 1: 151. https://doi.org/10.3390/molecules27010151

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