TY - JOUR AU - Serafin, Pawel AU - Szeleszczuk, Lukasz AU - Zhukov, Igor AU - Szűcs, Edina AU - Gombos, Dávid AU - Stefanucci, Azzurra AU - Mollica, Adriano AU - Pisklak, Dariusz Maciej AU - Kleczkowska, Patrycja TI - Opioid/Dopamine Receptor Binding Studies, NMR and Molecular Dynamics Simulation of LENART01 Chimera, an Opioid-Bombesin-like Peptide JF - MOLECULES J2 - MOLECULES VL - 29 PY - 2024 IS - 1 PG - 16 SN - 1420-3049 DO - 10.3390/molecules29010272 UR - https://m2.mtmt.hu/api/publication/34547382 ID - 34547382 AB - The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs (including enzymatic stability, efficacy and pharmacokinetic and pharmacodynamic profiles). In addition, considering various complex diseases and/or disorders, the conjugate chemistry approach is highly acceptable and justified. Opioids have long been recognized as the most potent analgesics and serve as the basic pharmacophore for potent hybrid compounds that may be useful in pain management. However, a risk of tolerance and physical dependence exists. Since dopamine receptors have been implicated in the aforementioned adverse effects of opioids, the construction of a hybrid with dual action at opioid and dopamine receptors is of interest. Herein, we present nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation results for LENART01, an opioid-ranatensin hybrid peptide. Apart from molecular docking, protein-ligand interactions were also assessed in vitro using a receptor binding assay, which proved LENART01 to be bound to mu-opioid and dopamine receptors, respectively. LA - English DB - MTMT ER - TY - JOUR AU - Ötvös, Ferenc AU - Szűcs, Edina AU - Urai, Ákos AU - Köteles, István AU - Szabó, Pál Tamás AU - Varga, Zsuzsanna Katalin AU - Gombos, Dávid AU - Hosztafi, Sándor AU - Benyhe, Sándor TI - Synthesis and biochemical evaluation of 17-N-beta-aminoalkyl-4,5α-epoxynormorphinans JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 13 PY - 2023 IS - 1 PG - 16 SN - 2045-2322 DO - 10.1038/s41598-023-46317-3 UR - https://m2.mtmt.hu/api/publication/34407138 ID - 34407138 N1 - Export Date: 25 February 2024 AB - Opiate alkaloids and their synthetic derivatives are still widely used in pain management, drug addiction, and abuse. To avoid serious side effects, compounds with properly designed pharmacological profiles at the opioid receptor subtypes are long needed. Here a series of 17- N -substituted derivatives of normorphine and noroxymorphone analogues with five- and six-membered ring substituents have been synthesized for structure–activity study. Some compounds showed nanomolar affinity to MOR, DOR and KOR in in vitro competition binding experiments with selective agonists [ 3 H]DAMGO, [ 3 H]Ile 5,6 -deltorphin II and [ 3 H]HS665, respectively. Pharmacological characterization of the compounds in G-protein signaling was determined by [ 35 S]GTPγS binding assays. The normorphine analogues showed higher affinity to KOR compared to MOR and DOR, while most of the noroxymorphone derivatives did not bind to KOR. The presence of 14-OH substituent resulted in a shift in the pharmacological profiles in the agonist > partial agonist > antagonist direction compared to the parent compounds. A molecular docking-based in silico method was also applied to estimate the pharmacological profile of the compounds. Docking energies and the patterns of the interacting receptor atoms, obtained with experimentally determined active and inactive states of MOR, were used to explain the observed pharmacological features of the compounds. LA - English DB - MTMT ER - TY - JOUR AU - Marinaccio, Lorenza AU - Zengin, Gokhan AU - Pieretti, Stefano AU - Minosi, Paola AU - Szűcs, Edina AU - Benyhe, Sándor AU - Novellino, Ettore AU - Masci, Domiziana AU - Stefanucci, Azzurra AU - Mollica, Adriano TI - Food-inspired peptides from spinach Rubisco endowed with antioxidant, antinociceptive and anti-inflammatory properties JF - FOOD CHEMISTRY: X J2 - FOOD CHEM X VL - 18 PY - 2023 PG - 7 SN - 2590-1575 DO - 10.1016/j.fochx.2023.100640 UR - https://m2.mtmt.hu/api/publication/34108334 ID - 34108334 N1 - Department of Pharmacy, G. d'Annunzio University of Chieti-Pescara, Chieti, 66100, Italy Department of Biology, Science Faculty, Selcuk University, Konya, 42130, Turkey National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome00161, Italy Institute of Biochemistry, Biological Research Centre, Szeged, 6726, Hungary NGN Healthcare, Mercogliano, 207, Via Nazionale Torrette83013, Italy Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of Sacred Heart, Largo Francesco Vito 1, Rome00168, Italy Cited By :6 Export Date: 22 February 2024 Correspondence Address: Stefanucci, A.; Department of Pharmacy, Italy; email: a.stefanucci@unich.it AB - Rubiscolin-6 (amino acid sequence: YPLDLF) is a selective & delta;-opioid receptor peptide isolated from spinach Rubisco. Its synthetic analogue, peptide YPMDIV is the most potent described so far for its increased opioid activity, thus in this work it was considered as lead compound for the design of twelve new analogues e.g. LMAS112. Firstly all the novel compounds have been tested for their antinociceptive and anti-inflammatory capacity in vitro and in vivo in order to evaluate their ability to maintain or loss the original activity. Among them peptides LMAS5-8 gave the best results, thus their antioxidant properties have been investigated along with their enzymatic inhibitory ability. Peptide LMAS6 shows a strong antioxidant (154.25 mg TE/g CUPRAC) and inhibitor activity on tyrosinase (84.49 mg KAE/g), indicating a potential role in food industry as anti-browning agent, while peptides LMAS5 and LMAS7 possess a modest cholinesterase inhibitory activity suggesting a conceivable use for nutraceuticals production. LA - English DB - MTMT ER - TY - JOUR AU - Karádi, Dávid Árpád AU - Galambos, Anna Rita AU - Lakatos, Péter Pál AU - Apenberg, Joost AU - Abbood, Sarah Kadhim AU - Balogh, Mihály AU - Király, Kornél P AU - Riba, Pál AU - Gomaa, Nariman Essmat Mohamed Aldeltawab AU - Szűcs, Edina AU - Benyhe, Sándor AU - Varga, Zoltán AU - Szökő, Éva AU - Tábi, Tamás AU - Al-Khrasani, Mahmoud TI - Telmisartan Is a Promising Agent for Managing Neuropathic Pain and Delaying Opioid Analgesic Tolerance in Rats JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 9 PG - 18 SN - 1661-6596 DO - 10.3390/ijms24097970 UR - https://m2.mtmt.hu/api/publication/33784924 ID - 33784924 AB - Despite the large arsenal of analgesic medications, neuropathic pain (NP) management is not solved yet. Angiotensin II receptor type 1 (AT1) has been identified as a potential target in NP therapy. Here, we investigate the antiallodynic effect of AT1 blockers telmisartan and losartan, and particularly their combination with morphine on rat mononeuropathic pain following acute or chronic oral administration. The impact of telmisartan on morphine analgesic tolerance was also assessed using the rat tail-flick assay. Morphine potency and efficacy in spinal cord samples of treated neuropathic animals were assessed by [35S]GTPγS-binding assay. Finally, the glutamate content of the cerebrospinal fluid (CSF) was measured by capillary electrophoresis. Oral telmisartan or losartan in higher doses showed an acute antiallodynic effect. In the chronic treatment study, the combination of subanalgesic doses of telmisartan and morphine ameliorated allodynia and resulted in a leftward shift in the dose–response curve of morphine in the [35S]GTPγS binding assay and increased CSF glutamate content. Telmisartan delayed morphine analgesic-tolerance development. Our study has identified a promising combination therapy composed of telmisartan and morphine for NP and opioid tolerance. Since telmisartan is an inhibitor of AT1 and activator of PPAR-γ, future studies are needed to analyze the effect of each component. LA - English DB - MTMT ER - TY - JOUR AU - Kozsurek, Márk AU - Király, Kornél P AU - Gyimesi, Klára AU - Lukácsi, Erika AU - Fekete, Csaba AU - Gereben, Balázs AU - Mohácsik, Petra AU - Helyes, Zsuzsanna AU - Bölcskei, Kata AU - Tékus, Valéria AU - Pap, Károly AU - Szűcs, Edina AU - Benyhe, Sándor AU - Imre, Timea AU - Szabó, Pál Tamás AU - Gajtkó, Andrea AU - Szentesiné Holló, Krisztina AU - Puskár, Zita TI - Unique, Specific CART Receptor-Independent Regulatory Mechanism of CART(55-102) Peptide in Spinal Nociceptive Transmission and Its Relation to Dipeptidyl-Peptidase 4 (DDP4) JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 2 PG - 25 SN - 1661-6596 DO - 10.3390/ijms24020918 UR - https://m2.mtmt.hu/api/publication/33560486 ID - 33560486 AB - Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia. LA - English DB - MTMT ER - TY - JOUR AU - Laskowska, Anna K. AU - Szudzik, Mateusz AU - Sciezynska, Aneta AU - Komorowski, Michal AU - Szűcs, Edina AU - Gombos, David AU - Baczek, Bartlomiej AU - Lipka-Miciuk, Jowita AU - Benyhe, Sándor AU - Kleczkowska, Patrycja TI - The Role of a Natural Amphibian Skin-Based Peptide, Ranatensin, in Pancreatic Cancers Expressing Dopamine D2 Receptors JF - CANCERS J2 - CANCERS VL - 14 PY - 2022 IS - 22 PG - 16 SN - 2072-6694 DO - 10.3390/cancers14225535 UR - https://m2.mtmt.hu/api/publication/33313345 ID - 33313345 N1 - Funding Agency and Grant Number: National Science Center (NCN) Miniatura 4 project [2020/04/X/NZ7/00146] Funding text: This study was supported by the National Science Center (NCN) Miniatura 4 project no. 2020/04/X/NZ7/00146. AB - Simple Summary Cancer is one of the most problematic issues worldwide, as it still requires effective therapy. Unfortunately, clinically available cancer-specific medications result in serious side effects. This is also true for pancreatic cancer which additionally is well-known for difficulties in the treatment. Therefore, the aim of the study was to evaluate the biological activity, in terms of anticancer effects, of ranatensin (RAN), a naturally existing bombesin-like peptide. For the first time, we characterized the peptide as a dopaminergic system ligand. However, despite the presence of dopamine receptors in pancreatic cancer cell lines used, RAN was found to affect cancer cells possibly through different receptors since RAN's impact on pancreatic cancer cells was not correlated with their expression level of DRD2. Nevertheless, this peptide may serve as a potential useful agent with therapeutic efficacy in cancers expressing DRD2 receptors, for which DRD2 antagonism is crucial to produce antitumor effects. Despite the progress in early diagnostic and available treatments, pancreatic cancer remains one of the deadliest cancers. Therefore, there is an urgent need for novel anticancer agents with a good safety profile, particularly in terms of possible side-effects. Recently dopaminergic receptors have been widely studied as they were proven to play an important role in cancer progression. Although various synthetic compounds are known for their interactions with the dopaminergic system, peptides have recently made a great comeback. This is because peptides are relatively safe, easy to correct in terms of the improvement of their physicochemical and biological properties, and easy to predict. This paper aims to evaluate the anticancer activity of a naturally existing peptide-ranatensin, toward three different pancreatic cancer cell lines. Additionally, since there is no sufficient information confirming the exact character of the interaction between ranatensin and dopaminergic receptors, we provide, for the first time, binding properties of the compound to such receptors. LA - English DB - MTMT ER - TY - JOUR AU - Stefanucci, Azzurra AU - Della, Valle Alice AU - Scioli, Giuseppe AU - Marinaccio, Lorenza AU - Pieretti, Stefano AU - Minosi, Paola AU - Szűcs, Edina AU - Benyhe, Sándor AU - Masci, Domiziana AU - Tanguturi, Parthasaradhireddy AU - Chou, Kerry AU - Barlow, Deborah AU - Houseknecht, Karen AU - Streicher, John M. AU - Mollica, Adriano TI - Discovery of kappa Opioid Receptor (KOR)-Selective D-Tetrapeptides with Improved In Vivo Antinociceptive Effect after Peripheral Administration JF - ACS MEDICINAL CHEMISTRY LETTERS J2 - ACS MED CHEM LETT VL - 13 PY - 2022 IS - 11 SP - 1707 EP - 1714 PG - 8 SN - 1948-5875 DO - 10.1021/acsmedchemlett.2c00237 UR - https://m2.mtmt.hu/api/publication/33221906 ID - 33221906 N1 - Funding Agency and Grant Number: MIUR-PRIN [2017PHRC8X_004]; NIH [R01DA052340] Funding text: This work was partially funded by MIUR-PRIN 2017 (2017PHRC8X_004) and NIH R01DA052340, provided to J.M.S. and K.H. AB - Peripherally active tetrapeptides as selective kappa opioid receptor (KOR) agonists have been prepared in good overall yields and high purity following solid-phase peptide synthesis via Fmoc protection strategy. Structural modifications at the first and second position of the lead compound FF(D-Nle)R-NH2 (FE200041) were contemplated with aromatic side chains containing D-amino acids, such as (D)-pF-Phe, (D)-mF-Phe, (D)-oF-Phe, which led to highly selective and efficacious KOR agonists endowed with strong antinociceptive activity in vivo following intravenous (i.v.) and subcutaneous (s.c.) administration in the tail flick and formalin tests. These results suggest potential clinical applications in the treatment of neuropathic and inflammatory pain. LA - English DB - MTMT ER - TY - JOUR AU - Mirdamadi, Seyedmohsen AU - Schaffer, Annamária AU - Barna, Tamara AU - Samavati, Reza AU - Szűcs, Kálmán Ferenc AU - Szűcs, Edina AU - Benyhe, Sándor AU - Szécsi, Mihály AU - Gáspár, Róbert TI - Non-genomic uterorelaxant actions of corticosteroid hormones in rats: An in vitro and in vivo study JF - EUROPEAN JOURNAL OF PHARMACOLOGY J2 - EUR J PHARMACOL VL - 935 PY - 2022 PG - 10 SN - 0014-2999 DO - 10.1016/j.ejphar.2022.175346 UR - https://m2.mtmt.hu/api/publication/33174887 ID - 33174887 N1 - Funding Agency and Grant Number: Ministry of Innovation and Technology of Hungary from the National Research, Development, and Innovation Fund; Stipendium Hungaricum Scholarship; [TKP2021-EGA-32]; [TKP2021-EGA] Funding text: Project No. TKP2021-EGA-32 was implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development, and Innovation Fund, financed under the TKP2021-EGA funding scheme. This work was also supported by the Stipendium Hungaricum Scholarship. Special thanks are due to ? Agnes Csisz ? arne ? for technical assistance in the experiments. LA - English DB - MTMT ER - TY - JOUR AU - Bálint, Emese Réka AU - Fűr, Gabriella AU - Kui, Balázs AU - Balla, Zsolt AU - Kormányos, Eszter Sára AU - Orján, Erik Márk AU - Tóth, Brigitta AU - Horváth, Gyöngyi AU - Szűcs, Edina AU - Benyhe, Sándor AU - Ducza, Eszter AU - Pallagi, Petra AU - Maléth, József AU - Venglovecz, Viktória AU - Hegyi, Péter AU - Kiss, Lóránd AU - Rakonczay, Zoltán TI - Fentanyl but Not Morphine or Buprenorphine Improves the Severity of Necrotizing Acute Pancreatitis in Rats JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 3 PG - 23 SN - 1661-6596 DO - 10.3390/ijms23031192 UR - https://m2.mtmt.hu/api/publication/32624010 ID - 32624010 N1 - Department of Pathophysiology, University of Szeged, Szeged, 6725, Hungary Department of Medicine, University of Szeged, Szeged, 6725, Hungary Department of Physiology, University of Szeged, Szeged, 6725, Hungary Institute of Biochemistry, Biological Research Center, Szeged, 6726, Hungary Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Szeged, 6725, Hungary Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, 6725, Hungary Institute for Translational Medicine, Medical School, University of Pecs, Pecs, 7624, Hungary Cited By :4 Export Date: 16 October 2023 Correspondence Address: Kiss, L.; Department of Pathophysiology, Hungary; email: lorand.kiss.work@gmail.com Correspondence Address: Rakonczay, Z.; Department of Pathophysiology, Hungary; email: rakonczay.zoltan@med.u-szeged.hu Chemicals/CAS: amylase, 9000-90-2, 9000-92-4, 9001-19-8; buprenorphine, 52485-79-7, 53152-21-9; ceruletide, 17650-98-5; enkephalin[2 dextro alanine 4 methylphenylalanine 5 glycine], 78123-71-4; fentanyl, 437-38-7, 1443-54-5; gentamicin, 1392-48-9, 1403-66-3, 1405-41-0; ketamine, 1867-66-9, 6740-88-1, 81771-21-3; morphine, 52-26-6, 57-27-2; myeloperoxidase; naloxone, 357-08-4, 465-65-6; ornithine, 70-26-8, 7006-33-9; taurocholic acid, 145-42-6, 59005-70-8, 81-24-3; xylazine, 23076-35-9, 7361-61-7; Analgesics, Opioid; Buprenorphine; Fentanyl; Morphine; Receptors, Opioid, mu Tradenames: PE-10, Becton Dickinson, United States; PE-10, Clay Adams, United States Manufacturers: CP Pharmaceuticals, Germany; Sigma Aldrich, HungaryBecton Dickinson, United States; Clay Adams, United States Funding text 1: Funding: This work was supported by EFOP-3.6.2–16–2017–00006, GINOP-2.3.2-15-2016-00048, Bólyai János Research Grant (BO/00866/20/5), ÚNKP Grant (ÚNKP-20-5-SZTE-163), NKFIH PD129114 and NKFIH K119938. The funders did not influence the interpretation of results in any way. AB - Opioids are widely used for the pain management of acute pancreatitis (AP), but their impact on disease progression is unclear. Therefore, our aim was to study the effects of clinically relevant opioids on the severity of experimental AP. Various doses of fentanyl, morphine, or buprenorphine were administered as pre- and/or post-treatments in rats. Necrotizing AP was induced by the intraperitoneal injection of L-ornithine-HCl or intra-ductal injection of Na-taurocholate, while intraperitoneal caerulein administration caused edematous AP. Disease severity was determined by laboratory and histological measurements. Mu opioid receptor (MOR) expression and function was assessed in control and AP animals. MOR was expressed in both the pancreas and brain. The pancreatic expression and function of MOR were reduced in AP. Fentanyl post-treatment reduced necrotizing AP severity, whereas pre-treatment exacerbated it. Fentanyl did not affect the outcome of edematous AP. Morphine decreased vacuolization in edematous AP, while buprenorphine pre-treatment increased pancreatic edema during AP. The overall effects of morphine on disease severity were negligible. In conclusion, the type, dosing, administration route, and timing of opioid treatment can influence the effects of opioids on AP severity. Fentanyl post-treatment proved to be beneficial in AP. Clinical studies are needed to determine which opioids are best in AP. LA - English DB - MTMT ER - TY - THES AU - Szűcs, Edina TI - Comparative biochemical and pharmacological investigations of various newly developed opioid receptor ligands [Különböző újonnan kifejlesztett opioid receptor ligandok összehasonlító biokémiai és farmakológiai vizsgálata] PB - Szegedi Tudományegyetem (SZTE) PY - 2021 SP - 66 DO - 10.14232/phd.10631 UR - https://m2.mtmt.hu/api/publication/32475872 ID - 32475872 LA - English DB - MTMT ER -