Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives

Adamska‐Bartłomiejczyk, Anna; Lipiński, Piotr F. J.; Piekielna-Ciesielska, Justyna; Kluczyk, Alicja; Janecka, Anna

doi:10.1002/cmdc.202000248

Cited by 6 publications

(10 citation statements)

References 42 publications

(52 reference statements)

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“…Similar binding poses were also proposed based on molecular modelling results for the opioid fragment of other opioid/antitachykinin hybrids [ 17 ] or some Tyr- d -Ala-Phe-Phe (TAPP) derivatives [ 66 ]. Aromatic rings of BU72 (experiment [ 67 ]), fentanyl (modelling [ 68 ]) cyclic opioid derivatives (modelling [ 69 ]), or linear peptide opioids (modelling [ 70 ]) were found to be located similarly as the Phe 4 ring in MOR-1 pose. For the -NH-NH-Z- d -Trp fragment, a few quite distinct binding poses are found at MOR.…”

Section: Resultsmentioning

confidence: 99%

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

Matalińska

Lipiński

Kossoń

et al. 2020

IJMS

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AA3266 is a hybrid compound consisting of opioid receptor agonist and neurokinin-1 receptor (NK1R) antagonist pharmacophores. It was designed with the desire to have an analgesic molecule with improved properties and auxiliary anticancer activity. Previously, the compound was found to exhibit high affinity for μ- and δ-opioid receptors, while moderate binding to NK1R. In the presented contribution, we report on a deeper investigation of this hybrid. In vivo, we have established that AA3266 has potent antinociceptive activity in acute pain model, comparable to that of morphine. Desirably, with prolonged administration, our hybrid induces less tolerance than morphine does. AA3266, contrary to morphine, does not cause development of constipation, which is one of the main undesirable effects of opioid use. In vitro, we have confirmed relatively strong cytotoxic activity on a few selected cancer cell lines, similar to or greater than that of a reference NK1R antagonist, aprepitant. Importantly, our compound affects normal cells to smaller extent what makes our compound more selective against cancer cells. In silico methods, including molecular docking, molecular dynamics simulations and fragment molecular orbital calculations, have been used to investigate the interactions of AA3266 with MOR and NK1R. Insights from these will guide structural optimization of opioid/antitachykinin hybrid compounds.

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Section: Resultsmentioning

confidence: 99%

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

Matalińska

Lipiński

Kossoń

et al. 2020

IJMS

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“…β-Peptides (made of only β-amino acids) in general do not appear in nature, though among the opioid peptides, there are examples of such synthetic analogs [ 27 ]. More often mixed α/β-peptides, in which one or more β-residues are incorporated instead of some α-amino acids, were constructed [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…In our former work [ 33 ], we devised an interaction model for RP-170 and its analogs, in which the peptides were anchored in the MOR binding pocket by interactions at the three key binding subsites. According to that model, in the S1 subsite, the protonable amino group of Tyr 1 interacts with Asp 147 (a typical contact for high-affinity MOR agonists of both peptide [ 24 ] and non-peptide character [ 38 ]).…”

Section: Discussionmentioning

confidence: 99%

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

Wtorek

Lipiński

Adamska‐Bartłomiejczyk

et al. 2021

Molecules

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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.

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“…Position 2 of EM has been modified successfully without damaging the affinity but improving the enzymatic hydrolysis resistance despite the reduction of MOR selectivity over DOR [ 111 , 136 , 142 , 240 , 259 ]. Likewise, many studies showed that the substitutions of various β-amino acids including acyclic β-amino acids into EMs were well tolerated at position 2, unlike the other positions [ 136 , 141 , 143 ].…”

Section: Peptidomimetics For Opioid Receptorsmentioning

confidence: 99%

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Lee

2022

Biomolecules

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Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures.

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Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives

Cited by 6 publications

References 42 publications

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

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

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

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