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A CB1 Receptor Antagonist As a Direct Interactional Partner for Μ- and Δ-Opioid Receptor

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A CB1 Receptor Antagonist As a Direct Interactional Partner for Μ- and Δ-Opioid Receptor Rimonabant: a CB1 receptor antagonist as a direct interactional partner for μ- and δ-opioid receptor Ph.D. thesis Ferenc Zádor Supervisor: Dr. Sándor Benyhe Institute of Biochemistry Biological Research Center of the Hungarian Academy of Sciences Szeged, Hungary 2014 TABLE OF CONTENTS LIST OF PUBLICATIONS ...................................................................................................... i LIST OF ABBREVIATIONS .................................................................................................. ii 1 REVIEW OF THE LITERATURE ................................................................................. 1 1.1 G-protein coupled receptors (GPCR) .............................................................................. 1 1.1.1 About GPCRs in general ................................................................................................................ 1 1.1.2 The structure of GPCRs ................................................................................................................. 3 1.1.3 The spectrum of GPCR ligand efficacy and constitutive activity of GPCRs ................................. 3 1.1.4 GPCR signaling: the G-protein activation/deactivation cycle ....................................................... 4 1.1.5 The complexity of GPCR signaling ............................................................................................... 6 1.2 Opioids and cannabinoids and their endogenous systems ............................................. 7 1.2.1 Opium poppy and the cannabis plant, opioids and cannabinoids................................................... 7 1.2.2 Opioid and cannabinoid receptors .................................................................................................. 7 1.2.3 The endogenous opioid and the endocannabinoid system ............................................................. 8 1.2.4 Opioid and cannabinoid receptor interactions .............................................................................. 10 1.3 Rimonabant ..................................................................................................................... 11 1.3.1 The CB1 receptor and appetite, Acomplia® ................................................................................. 11 1.3.2 The psychiatric side effects and unspecific actions of rimonabant .............................................. 11 1.3.3 Interactions of rimonabant with the opioid system ...................................................................... 12 2 AIMS OF THE STUDY .................................................................................................. 14 3 MATERIALS AND METHODS ................................................................................... 16 3.1 Chemicals ......................................................................................................................... 16 3.1.1 Radiochemicals ............................................................................................................................ 16 3.1.2 Receptor ligands and fine chemicals ............................................................................................ 16 3.2 Animals ............................................................................................................................. 17 3.3 Cell lines ........................................................................................................................... 17 3.4 Membrane preparations ................................................................................................. 18 3.4.1 Mouse forebrain membrane preparations ..................................................................................... 18 3.4.2 Cell line membrane preparations ................................................................................................. 18 3.5 In vitro binding assays ..................................................................................................... 19 3.5.1 The principles of in vitro binding assays ..................................................................................... 19 3.5.2 Radioligand competition binding assays ...................................................................................... 20 3.5.3 Functional [35S]GTPγS binding assays ........................................................................................ 21 3.6 Docking experiments ....................................................................................................... 23 3.7 Data analysis .................................................................................................................... 24 4 RESULTS ......................................................................................................................... 26 4.1 Direct binding affinity measurements ........................................................................... 26 4.1.1 Direct binding of rimonabant towards MOR in radioligand competition binding assays performed in wild type and CB1 K.O. mouse forebrain membranes ............................................ 26 4.1.2 Direct binding of rimonabant towards MOR and DOR in radioligand competition binding assays performed in CHO-rMOR or CHO-mDOR cell membranes ............................................ 28 4.1.3 Docking experiments with rimonabant to inactive and active MOR homology model ............... 31 4.2 MOR and DOR mediated G-protein activity measurements ...................................... 34 35 4.2.1 The effect of rimonabant on DOR G-protein basal activity in [ S]GTPγS binding assays, in CHO-mDOR and pCHO cell membranes .................................................................................... 34 35 4.2.2 The effect of rimonabant on DOR G-protein activation in DPDPE-stimulated [ S]GTPγS binding, in CHO-mDOR cell membranes .................................................................................... 36 4.2.3 The effect of rimonabant on MOR and DOR G-protein activation in agonist-stimulated 35 [ S]GTPγS binding, in wild type and CB1 and CB1/CB2 receptor double knock-out mouse forebrain membranes .................................................................................................................... 38 5 DISCUSSION .................................................................................................................. 43 6 SUMMARY ..................................................................................................................... 49 7 CONCLUDING REMARKS .......................................................................................... 50 8 REFERENCES ................................................................................................................ 51 9 WEB REFERENCES ...................................................................................................... 65 10 ACKNOWLEDGEMENTS ............................................................................................ 66 APPENDICES ........................................................................................................................ 68 Appendix A: Summary of the Ph.D. thesis in Hungarian ................................................. 69 Appendix B: Off-prints of thesis related publications ........................................................ 74 LIST OF PUBLICATIONS This thesis is based on the following publications: I. Zádor, F., Ötvös, F., Benyhe, S., Zimmer, A., Páldy, E. Inhibition of forebrain μ- opioid receptor signaling by low concentrations of rimonabant does not require cannabinoid receptors and directly involves μ-opioid receptors. Neurochem Int 61, 378-88 (2012). (2.66 impact factor) II. Zádor, 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. Neurochem Int 67, 14-22 (2014). (2.66 impact factor) Other publications unrelated to this thesis: Lackó, E., Váradi, A., Rapavi, R., Zádor, F., Riba, P., Benyhe, S., Borsodi, A., Hosztafi, S., Timár, J., Noszál, B., Fürst, S., Al-Khrasani, M. A novel µ-opioid receptor ligand with high in vitro and in vivo agonist efficacy. Curr Med Chem 19, 4699-707 (2012). (4.07 impact factor) Total impact factor: 9.39 ii LIST OF ABBREVIATIONS AC: ............................................................. adenylyl cyclase ADP-ribosylation: ...................................... adenosine diphosphate ribosylation AR.: ............................................................ adrenergic receptor BBB: ........................................................... blood-brain-barrier BMI: ........................................................... body mass index cAMP: .......................................................... adenosine 3',5'-cyclic mono-phosphate CB1 K.O.: ................................................... CB1 receptor knock-out CB1/ CB2 K.O.: ........................................... CB1/CB2 receptor double knock-out CB1: ............................................................ type 1 cannabinoid receptor CB2: ............................................................ type 2 cannabinoid receptor CHO: .......................................................... Chinese hamster ovary cell line CHO-mDOR: ............................................. Chinese hamster ovary cell line overexpressed with mouse -opioid receptor CHO-rMOR: ............................................... Chinese hamster
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