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

Karol Wtorek,Anna Janecka,Justyna Piekielna-Ciesielska,Anna Adamska-Bartłomiejczyk,Jarosław Sukiennik,Alicja Kluczyk,Piotr F J Lipiński

doi:10.3390/molecules27010151

Abstract

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.

Highlights

Among the three opioid receptors, mu (MOR), delta (DOR), and kappa (KOR), MOR plays the most important role in the modulation of pain signals and, is an important target in medicinal chemistry and drug development [1]
In order to obtain cyclic analogs based on the structure of EM-2 but still to preserve the free N-terminal amino group, we introduced into the sequence of EM-2 additional amino acids with functionalized side chains.into
We investigated the influence of a β-amino acid on the biological properties of RP-170

Summary

Introduction

Among the three opioid receptors, mu (MOR), delta (DOR), and kappa (KOR), MOR plays the most important role in the modulation of pain signals and, is an important target in medicinal chemistry and drug development [1]. The reduction in the ring size increased MOR selectivity [17]. Substitution of the Phe. The reduction in the ring size increased selectivity [17]. Phe residues by amino acids fluorinated in theMOR aromatic ring 4-CF residues by amino acids fluorinated in the aromatic ring (4-F-Phe, 2,4-diF-Phe, Phe) produced either high-affinity MOR/KOR agonists, non-selective MOR/DOR/KOR3agoproduced either high-affinity. KOR agonists [18], indicating that even small modifications in the side chains can completely change their orientation in the receptor cavity. D-Lys was replaced by (R)- or (S)-β3 -Lys, obtained by homologation of D- or L-ornitine (Orn) This modification produced compounds isomeric to RP-170 with of D- or L-ornitine (Orn). Opioid receptor binding and activation were studied, and the obtained results were rationalized receptor binding and activation were studied, and the obtained results were rationalized by molecular docking and molecular dynamics (MD) simulations

Methods

Results

Conclusion