15 results on '"Wtorek, Karol"'
Search Results
2. Historical Perspective and Current Trends in Anticancer Drug Development.
- Author
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Gach-Janczak, Katarzyna, Drogosz-Stachowicz, Joanna, Janecka, Anna, Wtorek, Karol, and Mirowski, Marek
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PROTEIN kinase inhibitors ,ANTINEOPLASTIC agents ,CHEMICAL reagents ,CELL proliferation ,APOPTOSIS ,CANCER chemotherapy ,MOLECULAR structure ,DRUG development ,ALKYLATING agents ,PHARMACODYNAMICS - Abstract
Simple Summary: Cancer is one of the leading causes of death worldwide. Among several therapeutic options available for patients, chemotherapy remains the most often used treatment strategy. Anticancer drugs known today are either substances isolated from plants and their derivatives or completely synthetic compounds. Some of them were discovered by accident, others as a result of long-term research. In this review, we present a brief history of the development of the main groups of anticancer drugs, focusing especially on their mode of action. This article also addresses the major side effects and limitations of currently available anticancer drugs and future perspectives in this area. Cancer is considered one of the leading causes of death in the 21st century. The intensive search for new anticancer drugs has been actively pursued by chemists and pharmacologists for decades, focusing either on the isolation of compounds with cytotoxic properties from plants or on screening thousands of synthetic molecules. Compounds that could potentially become candidates for new anticancer drugs must have the ability to inhibit proliferation and/or induce apoptosis in cancer cells without causing too much damage to normal cells. Some anticancer compounds were discovered by accident, others as a result of long-term research. In this review, we have presented a brief history of the development of the most important groups of anticancer drugs, pointing to the fact that they all have many side effects. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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3. Endomorphin-2 analogs containing modified tyrosines: Biological and theoretical investigation of the influence on conformation and pharmacological profile
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Wtorek, Karol, Artali, Roberto, Piekielna-Ciesielska, Justyna, Koszuk, Jacek, Kluczyk, Alicja, Gentilucci, Luca, and Janecka, Anna
- Published
- 2019
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4. Functional selectivity of EM-2 analogs at the mu-opioid receptor.
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Piekielna-Ciesielska, Justyna, Malfacini, Davide, Djeujo, Francine Medjiofack, Marconato, Chantal, Wtorek, Karol, Calo, Girolamo, and Janecka, Anna
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OPIOID receptors ,G protein coupled receptors ,FLUORESCENCE resonance energy transfer ,G proteins ,BIOLUMINESCENCE ,PAIN management ,SUMATRIPTAN - Abstract
The mu opioid receptor agonists are the most efficacious pain controlling agents but their use is accompanied by severe side effects. More recent developments indicate that some ligands can differentially activate receptor downstream pathways, possibly allowing for dissociation of analgesia mediated through the G protein from the opioid-related side effects mediated by ß-arrestin pathway. In an effort to identify such biased ligands, here we present a series of thirteen endomorphin-2 (EM-2) analogs with modifications in positions 1, 2, and/or 3. All obtained analogs behaved as mu receptor selective agonists in calcium mobilization assay carried out on cells expressing opioid receptors and chimeric G proteins. A Bioluminescence Resonance Energy Transfer (BRET) approach was employed to determine the ability of analogs to promote the interaction of the mu opioid receptor with G protein or ß-arrestin 2. Nearly half of the developed analogs showed strong bias towards G protein, in addition four compounds were nearly inactive towards ß-arrestin 2 recruitment while blocking the propensity of EM-2 to evoke mu-ß-arrestin 2 interaction. The data presented here contribute to our understanding of EM-2 interaction with the mu opioid receptor and of the transductional propagation of the signal. In addition, the generation of potent and selective mu receptor agonists strongly biased towards G protein provides the scientific community with novel tools to investigate the in vivo consequences of biased agonism at this receptor. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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5. Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors.
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Wtorek, Karol, Ghidini, Alessia, Gentilucci, Luca, Adamska-Bartłomiejczyk, Anna, Piekielna-Ciesielska, Justyna, Ruzza, Chiara, Sturaro, Chiara, Calò, Girolamo, Pieretti, Stefano, Kluczyk, Alicja, McDonald, John, Lambert, David G., and Janecka, Anna
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NOCICEPTIN , *OPIOID peptides , *OPIOID receptors , *MOLECULAR docking , *PEPTIDES , *MOTOR ability - Abstract
Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
6. Potential of Nociceptin/Orphanin FQ Peptide Analogs for Drug Development.
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Wtorek, Karol and Janecka, Anna
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- 2021
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7. Drug resistance in topoisomerase-targeting therapy.
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Wtorek, Karol, Długosz, Angelika, and Janecka, Anna
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DRUG resistance , *CANCER chemotherapy , *CANCER cells , *DNA topoisomerase II , *ANTHRACYCLINES - Abstract
Drug resistance is a well-known phenomenon that occurs when initially responsive to chemotherapy cancer cells become tolerant and elude further effectiveness of anticancer drugs. Based on their mechanism of action, anticancer drugs can be divided into cytotoxic-based agents and target-based agents. An important role among the therapeutics of the second group is played by drugs targeting topoisomerases, nuclear enzymes critical to DNA function and cell survival. These enzymes are cellular targets of several groups of anticancer agents which generate DNA damage in rapidly proliferating cancer cells. Drugs targeting topoisomerase I are mostly analogs of camtothecin, a natural compound isolated from the bark of a tree growing in China. Drugs targeting topoisomerase II are divided into poisons, such as anthracycline antibiotics, whose action is based on intercalation between DNA bases, and catalytic inhibitors that block topoisomerase II at different stages of the catalytic cycle. Unfortunately, chemotherapy is often limited by the induction of drug resistance. Identifying mechanisms that promote drug resistance is critical for the improvement of patient prognosis. Cancer drug resistance is a complex phenomenon that may be influenced by many factors. Here we discuss various mechanisms by which cancer cells can develop resistance to topoisomerase-directed drugs, which include enhanced drug efflux, mutations in topoisomerase genes, hypophosphorylation of topoisomerase II catalytic domain, activation of NF-κB transcription factor and drug inactivation. All these events may lead to the ineffective induction of cancer cell death. Attempts at circumventing drug resistance through the inhibition of cellular efflux pumps, use of silencing RNAs or inhibition of some important mechanisms, which can allow cancer cells to survive therapy, are also presented. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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8. Synthesis, Pharmacological Evaluation, and Computational Studies of Cyclic Opioid Peptidomimetics Containing β 3 -Lysine.
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Wtorek, Karol, Lipiński, Piotr F. J., Adamska-Bartłomiejczyk, Anna, Piekielna-Ciesielska, Justyna, Sukiennik, Jarosław, Kluczyk, Alicja, and Janecka, Anna
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OPIOID receptors , *PEPTIDOMIMETICS , *MOLECULAR dynamics , *IONIC interactions , *BINDING sites , *OPIOIDS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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9. Design, Synthesis and Functional Analysis of Cyclic Opioid Peptides with Dmt-Tic Pharmacophore.
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Sarkar, Arijit, Adamska-Bartlomiejczyk, Anna, Piekielna-Ciesielska, Justyna, Wtorek, Karol, Kluczyk, Alicja, Borics, Attila, Janecka, Anna, Sousa, Maria Emília de, Prokai-Tatrai, Katalin, Gomes, Paula A. C., Galdiero, Stefania, Gemma, Sandra, Spetea, Mariana, and Roivainen, Anne
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CYCLIC peptides ,FUNCTIONAL analysis ,SPATIAL arrangement ,OPIOID receptors ,OPIOID peptides ,PAIN perception ,LIGANDS (Biochemistry) - Abstract
The opioid receptors are members of the G-protein-coupled receptor (GPCR) family and are known to modulate a variety of biological functions, including pain perception. Despite considerable advances, the mechanisms by which opioid agonists and antagonists interact with their receptors and exert their effect are still not completely understood. In this report, six new hybrids of the Dmt-Tic pharmacophore and cyclic peptides, which were shown before to have a high affinity for the µ-opioid receptor (MOR) were synthesized and characterized pharmacologically in calcium mobilization functional assays. All obtained ligands turned out to be selective antagonists of the δ-opioid receptor (DOR) and did not activate or block the MOR. The three-dimensional structural determinants responsible for the DOR antagonist properties of these analogs were further investigated by docking studies. The results indicate that these compounds attach to the DOR in a slightly different orientation with respect to the Dmt-Tic pharmacophore than Dmt-TicΨ[CH
2 -NH]Phe-Phe-NH2 (DIPP-NH2 [Ψ]), a prototypical DOR antagonist peptide. Key pharmacophoric contacts between the DOR and the ligands were maintained through an analogous spatial arrangement of pharmacophores, which could provide an explanation for the predicted high-affinity binding and the experimentally observed functional properties of the novel synthetic ligands. [ABSTRACT FROM AUTHOR]- Published
- 2020
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10. The search for opioid analgesics with limited tolerance liability.
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Wtorek, Karol, Piekielna-Ciesielska, Justyna, Janecki, Tomasz, and Janecka, Anna
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OPIOID analgesics , *LIMITED liability , *OPIOID receptors , *SINGLE molecules , *OPIOID peptides , *G protein coupled receptors - Abstract
• Analgesic activity of morphine is associated with serious side effects. • One of these side effects is the development of tolerance. • Tolerance necessitates dose escalation resulting in a clinical vicious circle. • Analogs with MOR agonist/DOR antagonist profile attenuate tolerance development. • Peptides and peptidomimetics with such opioid receptor profile are described. Reducing the well-known side effects of opioids prescribed to treat chronic pain remains unresolved, despite extensive research in this field. Among several options to tackle this problem the synthesis of multifunctional compounds containing hybridized structures gained a lot of interest. Recently, extensively investigated are combinations of opioid agonist and antagonist pharmacophores embodied in a single molecule. To this end, agonism at the μ opioid receptor (MOR) with simultaneous antagonism at the δ opioid receptor (DOR) emerged as a promising avenue to obtaining novel analogs devoid of serious adverse effects associated with morphine-based analgesics. In this review we covered up-to-date research on the synthesis of peptide-based ligands with MOR agonist/DOR antagonist profile. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
11. Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors.
- Author
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Wtorek, Karol, Adamska-Bartłomiejczyk, Anna, Piekielna-Ciesielska, Justyna, Ferrari, Federica, Ruzza, Chiara, Kluczyk, Alicja, Piasecka-Zelga, Joanna, Calo', Girolamo, Janecka, Anna, Spetea, Mariana, and Schmidhammer, Helmut
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OPIOID receptors , *SUBSTANCE P receptors , *OPIOID analgesics , *SUBSTANCE P , *STRUCTURE-activity relationships , *DRUG side effects , *IN vivo studies - Abstract
Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure–activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
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12. Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors
- Author
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Karol Wtorek, Alessia Ghidini, Luca Gentilucci, Anna Adamska-Bartłomiejczyk, Justyna Piekielna-Ciesielska, Chiara Ruzza, Chiara Sturaro, Girolamo Calò, Stefano Pieretti, Alicja Kluczyk, John McDonald, David G. Lambert, Anna Janecka, Wtorek, Karol, Ghidini, Alessia, Gentilucci, Luca, Adamska-Bartłomiejczyk, Anna, Piekielna-Ciesielska, Justyna, Ruzza, Chiara, Sturaro, Chiara, Calò, Girolamo, Pieretti, Stefano, Kluczyk, Alicja, McDonald, John, Lambert, David G, and Janecka, Anna
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nociceptin receptor ,chimeric peptides ,Narcotic Antagonists ,Receptors, Opioid, mu ,Ligand ,docking studie ,opioid receptors ,calcium mobilization assay ,antitociceptive test ,docking studies ,chimeric peptide ,Ligands ,Peptides, Cyclic ,Catalysis ,Inorganic Chemistry ,Mice ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Analgesics ,Dose-Response Relationship, Drug ,Animal ,Naloxone ,Chimera ,Receptors, Opioid, kappa ,Organic Chemistry ,General Medicine ,opioid receptor ,Computer Science Applications ,Molecular Docking Simulation ,Analgesics, Opioid ,Peptide ,Receptors, Opioid ,Analgesic ,Peptides ,Narcotic Antagonist - Abstract
Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer.
- Published
- 2022
13. Synthesis, Pharmacological Evaluation, and Computational Studies of Cyclic Opioid Peptidomimetics Containing β 3 -Lysine.
- Author
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Wtorek K, Lipiński PFJ, Adamska-Bartłomiejczyk A, Piekielna-Ciesielska J, Sukiennik J, Kluczyk A, and Janecka A
- Subjects
- Analgesics, Opioid chemical synthesis, Animals, Binding Sites, Cell Line, Chemistry Techniques, Synthetic, Chromatography, Liquid, Humans, Mass Spectrometry, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Peptidomimetics chemical synthesis, Protein Binding, Receptors, Opioid chemistry, Receptors, Opioid metabolism, Structure-Activity Relationship, Analgesics, Opioid chemistry, Analgesics, Opioid pharmacology, Lysine chemistry, Models, Molecular, Peptides, Cyclic chemistry, Peptidomimetics chemistry, Peptidomimetics pharmacology
- Abstract
Our formerly described pentapeptide opioid analog Tyr-c[D-Lys-Phe-Phe-Asp]NH
2 (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.- Published
- 2021
- Full Text
- View/download PDF
14. Biased Agonism as an Emerging Strategy in the Search for Better Opioid Analgesics.
- Author
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Piekielna-Ciesielska J, Wtorek K, and Janecka A
- Subjects
- Analgesics, Analgesics, Opioid, Humans, Pain, Receptors, Opioid, Pain Management
- Abstract
Morphine and related drugs that act through activating opioid receptors are the most effective analgesics for the relief of severe pain. They have been used for decades, despite the range of unwanted side effects that they produce, as no alternative has been found so far. The major goal of opioid research is to understand the mechanism of action of opioid receptor agonists and to improve the therapeutic utility of opioid drugs. In the search for safer and more potent analgesics, analogs with mixed opioid receptor profile gained a lot of interest. However, recently the concept of biased agonism, that highlights the fact that some ligands are able to differentially activate receptor downstream pathways, became a new approach in the design of novel drug candidates for clinical application. In this review, we summarize current knowledge on the development of opioid ligands of peptide and nonpeptide structure, showing how much opioid pharmacology evolved in recent years., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2020
- Full Text
- View/download PDF
15. In vitro and in vivo activity of cyclopeptide Dmt-c[d-Lys-Phe-Asp]NH 2 , a mu opioid receptor agonist biased toward β-arrestin.
- Author
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Gach-Janczak K, Piekielna-Ciesielska J, Adamska-Bartłomiejczyk A, Wtorek K, Ferrari F, Calo' G, Szymaszkiewicz A, Piasecka-Zelga J, and Janecka A
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- Analgesics administration & dosage, Analgesics chemical synthesis, Analgesics chemistry, Analgesics, Opioid administration & dosage, Animals, Ligands, Mice, Morphine administration & dosage, Pain metabolism, Pain pathology, Peptides, Cyclic administration & dosage, Peptides, Cyclic chemical synthesis, Receptors, Opioid, mu agonists, Structure-Activity Relationship, beta-Arrestins genetics, Pain drug therapy, Peptides, Cyclic chemistry, Receptors, Opioid, mu metabolism, beta-Arrestins metabolism
- Abstract
Morphine and related drugs, which are the most effective analgesics for the relief of severe pain, act through activating opioid receptors. The endogenous ligands of these receptors are opioid peptides which cannot be used as antinociceptive agents due to their low bioactivity and stability in biological fluids. The major goal of opioid research is to understand the mechanism of action of opioid receptor agonists in order to improve therapeutic utility of opioids. Analgesic effects of morphine are mediated mostly through activation of the mu opioid receptor. However, in the search for safer and more effective drug candidates, analogs with mixed opioid receptor profile gained a lot of interest. Recently, the concept of biased agonists able to differentially activate GPCR downstream pathways, became a new approach in the design of novel drug candidates. It is hypothesized that compounds promoting G-protein signaling may produce analgesia while β-arrestin recruitment may be responsible for opioid side effects. In this report we showed that replacement of the tyrosine residue in the mu-selective ligand Tyr-c[d-Lys-Phe-Asp]NH
2 with 2',6'-dimethyltyrosine (Dmt) produced a cyclopeptide Dmt-c[d-Lys-Phe-Asp]NH2 with mu/delta opioid receptor agonist profile. This analog showed improved antinociception in the hot-plate test, probably due to the simultaneous activation of mu and delta receptors but also significantly inhibited the gastrointestinal transit. Using the bioluminescence resonance energy transfer (BRET) assay it was shown that this analog was a mu receptor agonist biased toward β-arrestin. β-Arrestin-dependent signaling is most likely responsible for the observed inhibition of gastrointestinal motility exerted by the novel cyclopeptide., (Copyright © 2018. Published by Elsevier Inc.)- Published
- 2018
- Full Text
- View/download PDF
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