Cellular and molecular interactions of bivalent ligands with oligomer receptors  Page description

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Details of project

 
Identifier
108518
Type K
Principal investigator Benyhe, Sándor
Title in Hungarian Oligomer receptorok és bivalens ligandok celluláris és molekuláris kölcsönhatásai
Title in English Cellular and molecular interactions of bivalent ligands with oligomer receptors
Keywords in Hungarian G-protein kapcsolt receptorok, internalizáció, bivalens ligandok, bifunkciós neuropeptidek, természetes és szintetikus opioidok
Keywords in English G-protein coupled receptors, receptor internalization, bivalent ligands, bifunctional neuropeptides, endogenous and synthetic opioids
Discipline
Molecular and cellular neuroscience (Council of Medical and Biological Sciences)34 %
Ortelius classification: Neurobiology
Signal transduction (Council of Medical and Biological Sciences)33 %
Experimental pharmacology, drug discovery and design (Council of Medical and Biological Sciences)33 %
Ortelius classification: Drug diseases
Panel Neurosciences
Department or equivalent Institute of Biochemistry (Biological Research Centre Szeged)
Participants Magyar, Anna
Mahmoud Al, Khrasani
Ötvös, Ferenc
Szűcs, Edina
Zádor, Ferenc
Starting date 2013-09-01
Closing date 2017-08-31
Funding (in million HUF) 41.082
FTE (full time equivalent) 7.60
state running project





 

Final report

 
Results in Hungarian
Alapvető célunk olyan nagy szelektivitású, kettős támadáspontú receptor ligandok szintézise, radiojelölése és jellemzése volt, amelyek jól hasznosíthatóak az opioid receptor rendszer kutatásában, másrészt a fájdalomcsillapítás új, nem-opiát hatóanyagainak fejlesztését segíthetik elő. Lényeges feladatnak tekintettük a fájdalomcsillapítás egy újszerű lehetőségére épülő, az idegrendszerben is kimutatott funkcionális receptor dimereket célzó kutatás-fejlesztést. Molekuláris távtartóval (spacer) kapcsoltuk össze a MOP receptor agonista Tyr-Gly-Gly-Phe tetrapeptidet a NOP receptor általunk kifejlesztett parciális agonista / antagonista hexapeptidjével, az Ac-RYYRIK-NH2 molekulával. A bivalens (hibrid) ligandok alkalmasak lehetnek a receptor dimerek kimutatására, továbbá egy jelentősen megnövekedett antinociceptív hatás közvetítésére. A megvalósult kutatás adatokat nyújtott a fájdalom fiziológiájában részt vevő neuropeptidek és receptoraik molekuláris hatásmechanizmusáról, receptor-receptor kölcsönhatásokról és az intracelluláris jelátviteli folyamatokról. E működések jobb megismerése elősegítheti a fájdalom-terápiában, a drogellenes küzdelem során hasznosuló, de más egészségügyi szempontból fontos, illetve orvosbiológiai vonatkozású tudományos ismeretanyag bővülését.
Results in English
The objective of the research project was to provide a detailed molecular and functional description of novel peptide-based communication pathways that are thought to modulate a number of physiological and pathological processes including pain, mood, and autonomic functions in the central nervous system. Novel peptide ligands for the opioid and nociceptin receptors, including structural analogues, selective antagonists, radioprobes were developed and studied by means of synthetic-chemical and functional-biochemical methods. Numerous studies have established the presence of G-protein coupled receptors (GPCRs) as dimers in heterologous cell expression systems but also in vivo. In this context, heterodimers of opioid receptors would constitute new targets of specific interest, each entity possessing original properties in terms of function and pharmacology. Mu opioid receptor (MOPr) activation induces analgesia, while NOPr activation would produce hyperalgesia. Thus, in order to fight pain, it would be important to synthesize one molecule combining the agonist effect for the MOP and antagonist for the NOPr receptors, in order to reinforce the synergistic effect on analgesia. The objective of this project was to conceive new analgesic molecules by combining two pharmacophores targeting the MOPr/NOPr and other heterodimers. These bivalent ligands would be part of a new generation of drugs, at least as efficient as morphine and maybe deprived of some side effects.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=108518
Decision
Yes





 

List of publications

 
Zador F, Kocsis D, Borsodi A, Benyhe S: Micromolar concentrations of rimonabant directly inhibits delta opioid receptor specific ligand binding and agonist-induced G-protein activity, Neurochemistry International 67 (2014) 14–22, 2014
Bojnik E, Kleczkowska P, de Velasco EMF, Corbani M, Babos F, Lipkowski AW, Magyar A, Benyhe S: Bioactivity studies on atypical natural opioid hexapeptides processed from proenkephalin (PENK) precursor polypeptides, COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY, 174: 29-35., 2014
Benyhe Zs, Tóth G, Wollemann M, Borsodi A, Helyes Zs, Rougeot C, Benyhe S: Effects of synthetic analogues of human opiorphin on rat brain opioid receptors., J Physiol Pharmacol. 65(4):525-530., 2014
Szlavicz E, Perera PS, Tömböly Cs, Helyes Zs, Zádor F, Benyhe S, Borsodi A, Bojnik E: Further characterization of hemopressin peptide fragments in the opioid and cannabinoid system, Anesthesia & Analgesia, 2015
Zador F, Lénárt N, Csibrány B, Sántha M, Molnár M, Tuka B, Samavati R, Klivényi P, Vécsei L, Marton A, Vizler Cs, Nagy NGy, Borsodi A, Benyhe S, Páldy E: Low dosage of rimonabant leads to anxiolytic-like behavior via inhibiting expression levels and G-protein activity of kappa-opioid receptors in a cannabinoid receptor ind, Neuropharmacology, 89:298-307, 2015
Benyhe S, Zádor F, Ötvös F: Biochemistry of opioid (morphine) receptors: binding, structure and molecular modelling, Acta Biologica Szegediensis, 59(Suppl.1):14-37., 2015
Mollica A, Costante R, Novellino E, Stefanucci A, Pieretti S, Zádor F, Samavati R, Borsodi A, Benyhe S, Vetter I, Lewis RJ: Design, Synthesis and Biological Evaluation of Two Opioid Agonist and Cav2.2 Blocker Multitarget Ligands, Chem Biol Drug Design 86:156-162., 2015
Judit Hajagos-Tóth, Judit Bóta, Eszter Ducza, Adrienn Csányi, Zita Tiszai, Anna Borsodi, Reza Samavati, Sándor Benyhe, Róbert Gáspár: The effects of estrogen on the α2-adrenergic receptor subtypes in rat uterine function in late pregnancy in vitro, Croat Med J. 2016;57:100-9, 2016
Judit Hajagos-Tóth, Judit Bóta, Eszter Ducza, Reza Samavati, Anna Borsodi, Sándor Benyhe and Róbert Gáspár: The effects of progesterone on the alpha2-adrenergic receptor subtypes in late-pregnant uterine contractions in vitro, Reproductive Biology and Endocrinology 14:33, 2016
Kleczkowska P, Hermans E, Kosson P, Kowalczyk A, Lesniak A, Pawlik K, Bojnik E, Benyhe S, Nowicka B, Bujalska-Zadrozny M, Misicka A, Lipkowski AW.: Antinociceptive effect induced by a combination of opioid and neurotensin moieties vs. their hybrid peptide [Ile(9)]PK20 in an acute pain treatment in rodents., Brain Res. 1648(Pt A):172-80., 2016
Agnieszka Kowalczyk, Patrycja Kleczkowska, Monika Rękaweka, Kamila Kulika, Anna Lesniaka, Anna Erdei, Attila Borics, Charlotte Martinc, Karolina Pawlika, Andrzej W. Lipkowskid, Sándor Benyhe, Helena Makulska-Nowaka, Steven Ballet, Magdalena Bujalska-Zadroznya: Biological evaluation and molecular docking studies of AA3052, a compound containing a -selective opioid peptide agonist DALDA and D-Phe-Phe-D-Phe-Leu-Leu-NH2, a substan, Eur J Pharm Sci. 93:11-20., 2016
I. LENGYEL, F. TOTH, D. BIYASHEV, I. SZATMARI, K. MONORY, C. TOMBOLY, G. TOTH, S. BENYHE, A. BORSODI: A NOVEL NON-OPIOID BINDING SITE FOR ENDOMORPHIN-1, J. Physiol. Pharmacol (Krakow), 2016
Ludovica Monti, Azzurra Stefanucci, Stefano Pieretti, Francesca Marzoli, Lorenzo Fidanza, Adriano Mollica, Sako Mirzaie, Simone Carradori, Luciano De Petrocellis, Aniello Schiano Moriello, Sándor Benyhe, Ferenc Zádor, Edina Szűcs, Ferenc Ötvös, Anna I. Erdei, Reza Samavati, Szabolcs Dvorácskó, Csaba Tömböly & Ettore Novellino: Evaluation of the analgesic effect of 4- anilidopiperidine scaffold containing ureas and carbamates, Journal of Enzyme Inhibition and Medicinal Chemistry, 2016
Edina Szucs, Alexandra Büki, Gabriella Kékesi, Gyöngyi Horváth, Sándor Benyhe: Mu-Opioid (MOP) receptor mediated G-protein signaling is impaired in specific brain regions in a rat model of schizophrenia, Neuroscience Letters 619 29–33, 2016
Edina Szucs, Szabolcs Dvorácskó, Csaba Tömböly, Alexandra Büki, Gabriella Kékesi, Gyöngyi Horváth, Sándor Benyhe: Decreased CB receptor binding and cannabinoid signaling in three brain regions of a rat model of schizophrenia, Neuroscience Letters 633 87–93, 2016
Tóth F, Mallareddy JR, Tourwé D, Lipkowski AW, Bujalska-Zadrozny M, Benyhe S, Ballet S, Tóth G, Kleczkowska P.: Synthesis and binding characteristics of [3H]neuromedin N, a NTS2 receptor ligand, Neuropeptides 57:15-20., 2016
Adriano Mollica, Sveva Pelliccia, Valeria Famiglini, Azzurra Stefanucci, Giorgia Macedonio, Annalisa Chiavaroli, Giustino Orlando, Luigi Brunetti, Claudio Ferrante, Stefano Pieretti, Ettore Novellino, Sandor Benyhe, Ferenc Zador, Anna Erdei, Edina Szucs, Reza Samavati, Szabolcs Dvoracsko, Csaba Tomboly, Rino Ragno, Alexandros Patsilinakos & Romano Silvestri: Exploring the first Rimonabant analog-opioid peptide hybrid compound, as bivalent ligand for CB1 and opioid receptors, Journal of Enzyme Inhibition and Medicinal Chemistry, 2017
Ferenc Zádor, Mihály Balogh, András Váradi, Zoltán S. Zádori, Kornél Király, Edina Szűcs, Bence Varga, Bernadette Lázár, Sándor Hosztafi, Pál Riba, Sándor Benyhe, Susanna Fürst, Mahmoud Al-Khrasani: 14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity, European Journal of Pharmacology, 2017
Ferenc Zádor, Kornél Király, András Váradi, Mihály Balogh, Ágnes Fehér, Dóra Kocsis, Anna I. Erdei, Erzsébet Lackó, Zoltán S. Zádori, Sándor Hosztafi, Béla Noszál, Pál Riba, Sándor Benyhe, Susanna Fürst, Mahmoud Al-Khrasani: New opioid receptor antagonist: Naltrexone-14-O-sulfate synthesis and pharmacology, European Journal of Pharmacology, 2017
Azzurra Stefanucci, Ettore Novellino, Sako Mirzaie, Giorgia Macedonio, Stefano Pieretti, Paola Minosi, Edina Szűcs Anna I. Erdei, Ferenc Zádor, Sándor Benyhe, and Adriano Mollica: Opioid Receptor Activity and Analgesic Potency of DPDPE Peptide Analogues Containing a Xylene Bridge, ACS Medicinal Chemistry Letters, 2017
Azzurra Stefanucci, Alfonso Carotenuto, Giorgia Macedonio, Ettore Novellino, Stefano Pieretti, Francesca Marzoli, Edina Szűcs, Anna I. Erdei, Ferenc Zádor, Sándor Benyhe, and Adriano Mollica: Cyclic Biphalin Analogues Incorporating a Xylene Bridge: Synthesis, Characterization, and Biological Profile, ACS Medicinal Chemistry Letters, 2017
Reza Samavati, Ferenc Zádor, Edina Szűcs, Bernadett Tuka, DiánaMartos, Gábor Veres, Róbert Gáspár, István M. Mándity, Ferenc Fülöp, László Vécsei, Sándor Benyhe, Anna Borsodi: Kynurenic acid and its analogue can alter the opioid receptor G-protein signaling after acute treatment via NMDA receptor in rat cortex and striatum, Journal of the Neurological Sciences, 2017
Gábor Nagy-Grócz, Ferenc Zádor,, Szabolcs Dvorácskó, Zsuzsanna Bohár, Sándor Benyhe, Csaba Tömböly, Árpád Párdutz and László Vécsei: Interactions between the Kynurenine and the Endocannabinoid System with Special Emphasis on Migraine, International Journal of Molecular Sciences, 2017
Anna I. Erdei, Adina Borbély, Anna Magyar, Nóra Taricska, András Perczel, Ottó Zsíros, Győző Garab, Edina Szűcs, Ferenc Ötvös, Ferenc Zádor, Mihály Balogh, Mahmoud Al-Khrasani, Sándor Benyhe: Biochemical and pharmacological characterization of three opioid-nociceptin hybrid peptide ligands reveals substantially differing modes of their actions, Peptides, 2017





 

Events of the project

 
2016-01-18 16:30:00
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