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Synthesis, Biochemical, Pharmacological Characterization and in Silico Profile Modelling of Highly Potent Opioid Orvinol and Thevinol Derivatives

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Synthesis, Biochemical, Pharmacological Characterization and in Silico Profile Modelling of Highly Potent Opioid Orvinol and Thevinol Derivatives Comparative biochemical and pharmacological investigations of various newly developed opioid receptor ligands Ph.D. thesis Edina Szűcs Supervisor: Sándor Benyhe, PhD, DSc Institute of Biochemistry, Biological Research Centre, Szeged Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged Szeged, Hungary 2020 i TABLE OF CONTENTS LIST OF PUBLICATIONS .......................................................................................... iii ACKNOWLEDGEMENTS ......................................................................................... vii LIST OF ABBREVIATIONS ....................................................................................... ix 1 INTRODUCTION ............................................................................................... 1 1.1 G-protein coupled receptors (GPCRs) .......................................................... 1 1.1.1 About GPCRs in general ...................................................................... 1 1.1.2 The structure of GPCRs ....................................................................... 1 1.1.3 GPCR signalling ................................................................................... 2 1.1.3.1 Gα signalling ................................................................................. 3 1.1.3.2 G signalling ................................................................................. 4 βγ 1.2 The opioid system ....................................................................................... 4 1.2.1 Poppy plant ......................................................................................... 4 1.2.2 Opioid receptors ................................................................................. 4 1.2.3 Opioid ligands ..................................................................................... 5 1.3 Kynurenines ................................................................................................. 6 1.3.1 The kynurenine pathway .................................................................... 6 1.3.2 KYNA receptors ................................................................................... 8 1.3.3 Kyn and KYNA ..................................................................................... 8 1.4 Pain ............................................................................................................ 10 1.4.1 Pain in general .................................................................................. 10 1.4.2 Opioid system and pain .................................................................... 11 1.4.3 KYNA and pain .................................................................................. 13 1.5 Approaches to overcome opioid side-effects ............................................ 14 1.5.1 Bentley analogues ............................................................................. 14 1.5.2 Oligopeptides .................................................................................... 16 2 AIMS OF THE STUDY ...................................................................................... 18 3 MATERIALS AND METHODS ............................................................................ 19 3.1 Chemicals .................................................................................................. 19 3.1.1 Radiochemicals ................................................................................. 19 3.1.2 Receptor ligands and fine chemicals ................................................ 19 3.2 Animals ...................................................................................................... 20 3.2.1 In vitro studies .................................................................................. 20 ii 3.2.2 In vivo studies with Bentley analogues ............................................. 20 3.2.3 In vivo studies with oligopeptides .................................................... 20 3.3 In vitro binding experiments ..................................................................... 21 3.3.1 Preparation of brain samples for binding assays ............................. 21 3.3.2 The principles of in vitro binding assays ......................................... 21 3.3.2.1 Competition binding experiments ............................................. 22 3.3.2.2 Functional [35S]GTPγS binding experiments ................................ 23 3.4 Chronic inflammatory pain model and measuring allodynia .................... 23 3.5 Formalin test: a model for acute inflammatory pain ................................. 24 3.6 Data analysis.............................................................................................. 25 3.6.1 In vitro experiments .......................................................................... 25 3.6.2 In vivo experiments with Bentley analogues ..................................... 25 3.6.3 In vivo experiments with oligopeptides ............................................ 25 4 RESULTS ......................................................................................................... 26 4.1 Competition binding assay ........................................................................ 26 4.1.1 Bentley analogues ............................................................................. 26 4.1.2 Oligopeptides .................................................................................... 29 4.2 Functional [35S]GTPS binding stimulation assay ....................................... 32 4.2.1 Bentley analogues ............................................................................. 32 4.2.2 Oligopeptides .................................................................................... 36 4.3 Inflammatory pain model .......................................................................... 40 4.3.1 Bentley analogues ............................................................................. 40 4.3.2 Oligopeptides .................................................................................... 43 5 DISCUSSION ................................................................................................... 44 6 SUMMARY ....................................................................................................... 49 7 FINAL REMARKS ............................................................................................. 50 8 REFERENCES ................................................................................................... 51 APPENDIX: OFF-PRINTS OF THE THESIS RELATED PUBLICATIONS ........................ 67 iii LIST OF PUBLICATIONS This thesis is based on the following publications: I. Edina Szűcs, János Marton, Zoltán Szabó, Sándor Hosztafi, Gabriella Kékesi, Gábor Tuboly, László Bánki, Gyöngyi Horváth, Pál T. Szabó, Csaba Tömböly, Zsuzsanna Varga, Sándor Benyhe, Ferenc Ötvös (2020) Synthesis, biochemical, pharmacological characterization and in silico profile modelling of highly potent opioid orvinol and thevinol derivatives. EUR. J. MED. CHEM., 191:1121-45. (5.572 impact factor, Q1) II. Edina Szűcs, Azzurra Stefanucci, Marilisa Pia Dimmito, Ferenc Zádor, Stefano Pieretti, Gokhan Zengin, László Vécsei, Sándor Benyhe, Adriano Mollica (2020) Discovery of Kynurenines containing oligopeptides as potent opioid receptor agonists. BIOMOLECULES, 10:1-18. (4.082 impact factor, Q1) Sum of the impact factors related to the thesis: 9.654 Other thematic publications not directly connected to this thesis: 1. Szűcs, E., Büki, A., Kékesi, G., Horváth, G., Benyhe, S. (2016) Mu-Opioid (MOP) receptor mediated G-protein signaling is impaired in specific brain regions in a rat model of schizophrenia. NEUROSCI. LETTERS, 619: 29-33. (2.180 impact factor, Q3) 2. Monti, L., Stefanucci, A., Pieretti, S., Marzoli, F., Fidanza, L., Mollica, A., Mirzaie, S., Carradori, S., De Petrocellis, L., Schiano Moriello, A., Benyhe, S., Zádor, F., Szűcs, E., Ötvös, F., Erdei, A.I., Samavati, R., Dvorácskó, S., Tömböly, C., Novellino, E. (2016) Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates. J. ENZYME INHIB. MED. CHEM., 31: 1638-47. (4.293 impact factor, Q2) iv 3. Szűcs, E., Dvorácskó, S., Tömböly, C., Büki, A., Kékesi, G., Horváth, G., Benyhe, S. (2016) Decreased CB receptor binding and cannabinoid signaling in three brain regions of a rat model of schizophrenia. NEUROSCI. LETTERS, 633: 87-93. (2.180 impact factor, Q3) 4. Mollica, A., Pelliccia, S., Famiglini, V., Stefanucci, A., Macedonio, G., Chiavaroli, A., Orlando, G., Brunetti, L., Ferrante, C., Pieretti, S., Novellino, E., Benyhe, S., Zador, F., Erdei, I.A., Szűcs, E., Samavati, R., Dvorácskó, S., Tömböly, C., Ragno, R., Patsilinakos, A., Silvestri, R. (2017) Exploring the first Rimonabant analog-opioid peptide hybrid compound, as bivalent ligand for CB1 and opioid receptors. J. ENZYME INHIB. MED. CHEM., 32: 444-451. (3.638 impact factor, Q2) 5. Zádor F, Balogh M, Váradi A, Zádori S Z, Király K, Szűcs E, Varga B, Lázár B, Hosztafi S, Riba P, Benyhe, S, Fürst S, Al-Khrasani M. (2017) 14-O-Methylmorphine: A Novel selective mu-opioid receptor agonist with high efficacy and affinity. EUR. J. PHARMACOL., 814: 264-273. (3.040 impact factor, Q1) 6. Samavati, R., Zádor, F., Szűcs, E., Tuka, B., Martos, D., Veres, G., Gáspár, R., Mándity, I.M., Fülöp, F., Vécsei, L., Benyhe, S., Borsodi, A. (2017) Kynurenic acid and its analogue can alter the opioid receptor G-protein signaling after acute treatment via NMDA receptor in rat cortex and striatum.
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