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Allosteric Modulation of GABAA Receptors by Steroids and Related

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Department of Pharmacology, School of Pharmacy, University of London, 29/39 Brunswick square, London WCIN lAX, UK ALLOSTERIC MODULATION OF GABA^ RECEPTORS BY STEROIDS AND RELATED COMPOUNDS: FUNCTIONAL AND BINDING STUDIES Yu Zhong, B.Sc. A thesis submitted for the Degree of Doctor of Philosophy University of London December, 1996 ProQuest Number: 10104782 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10104782 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 To my parents Aygr — ABSTRACT The allosteric modulation of GABA^ receptors by neuroactive steroids and related conpounds was investigated, using ^H-flunitrazepam binding to syn^tic membranes prepared from rat whole brain and electrophysiological recording from rat cuneate nucleus in a grease-g^ apparatus. The enhancement of ^H-flunitrazepam binding by pregnanolone, a reduced metabolite of progesterone, involves GABA-dependent and GABA-independent conponents. A low affinity conponent of pregnanolone's action is selectively antagonised by 11-ketoprogesterone. However, progesterone itself antagonises both high and low affinity conponents with only a slight selectivity against the low affinity conponent. Pregnenolone, the precursor of progesterone, has no effect while epipregnanolone, the Sp analogue of pregnanolone, causes a smaU general depression of the effects of pregnanolone. The properties described above strongly suggest multiple binding sites for pregnanolone on GABA^ receptors. The binding sites for pregnanolone are separate from those for propofol, vfiich enhances ^H-flunitrazepam binding in a largely GABA-independent manner that is not sensitive to 11-ketoprogesterone. The enhancement of ^H-flunitrazepam binding by A^^- alphaxalone is quite different from the enhancement by pregnanolone and propofol. It is GABA-dependent, with similar potency and efficacy to alphaxalone, but less potent and much less efficacious than pregnanolone. However, the interactions between pairs of steroids when used in combination suggest that A^-alphaxalone may share the same range of binding sites as pregnanolone and alphaxalone. Conpared with chlormethiazole and pentobarbitone, loreclezole is the most efficacious enhancer of ^H-flunitrazepam binding. The enhancement by loreclezole is due to an increase m binding affinity, is largely GABA-independent and can be partially blocked by chlormethiazole. However, chlormethiazole and pentobarbitone are more efficacious than loreclezole in potentiating responses to muscimol in cuneate nucleus slices. The interactions among loreclezole, chlormethiazole and pentobarbitone suggest separate sites of action for them on the GABAy^ receptor cortplex. TABLE OF CONTENTS ABSTRACT 3 TABLE OF CONTENTS 4 LIST OF FIGURES 10 LIST OF TABLES 13 Chapter 1: GENERAL INTRODUCTION 14 1.1. WHEN WAS GABA ESTABLISHED AS A 15 NEUROTRANSMTIER? 1.2. WHERE ARE GABA^ RECEPTORS? 17 1.3. WHAT ARE GABA^ RECEPTORS? 18 1.3.1. The structures of GABA^ receptors 18 1.3.2. The modulators of GABA^ receptors 21 1.4. STEROID MODULATION OF GABA^ RECEPTORS 26 1.4.1. What are neuroactive steroids? 26 1.4.2. Structure-activity relationship for steroids on GABA^ receptors 28 1.4.3. Sites of action for steroids 29 1.5. WHY THIS PROJECT? 34 Chapter 2: MATERIALS AND METHODS 42 2.1. RADIOLIGAND BINDING EXPERIMENTS 43 2.1.1. Background 43 2.1.2. Membrane preparation 46 2.1.3. Assays 48 2.1.4. Variations in the solvents used 50 2.1.5. Quantification of bound radioactivity 51 2.1.6. Data analysis 51 2.2. ELECTROPHYSIOLOGICAL STUDIES 53 2.2.1. Background 53 2.2.2. Preparation of rat cuneate nucleus slices 54 2.2.3. Tissue bath, perfusion and recording system 54 2.2.4. Quantification of drug effects 55 2.3. BUFFERS AND CHEMICALS USED 57 2.3.1. Buffers used for binding experiments 57 2.3.2. Buffers used for electrophysiological studies 57 2.3.3. Sources for dmgs and chemicals 57 Chapter 3: CHARACTERIZAHON OF MULHPLE COMPONENTS IN THE 63 ENHANCEMENT BY PREGNANOLONE AND PROPOFOL OF ^H-FLUNITRAZEPAM BINDING TO GABA^ RECEPTORS 3.1. INTRODUCTION 64 3.1.1. Steroids and GABA^ receptors 3.1.2. Propofol and GABA^ receptors 3.1.3. Biphasic neurosteroid concentration dependencies 3.1.4. Aim of this study 3.2. METHODS 67 3.3. RESULTS 68 3.3.1. Effects of 11-ketoprogesterone on the enhancement of 68 ^H-flunitrazepam binding by pregnanolone and propofol 3.3.2. Effects of bicucuUine and muscimol on the enhancement of 70 ^H-flunitrazepam binding by pregnanolone, propofol and the interaction of 11-ketoprogesterone and pregnanolone 3.4. DISCUSSION 79 3.5. CONCLUSIONS 81 Chapters 4: EFFECTS OF PROGESTERONE, EPIPREGNANOLONE; 83 PREGNENOLONE ON THE ENHANCEMENT BY PREGNANOLONE OF U-FLUNITRAZEPAM BINDING 4.1. INTRODUCnON 84 4.1.1. Structure-activity relationship of steroids 4.1.2. Evidences for multiple corqponents in steroids action 4.1.3. Aim of this study 4.2. METHODS 87 4.3. RESULTS 88 4.3.1. Effects of progesterone on the enhancement of U-fiunitrazepam 88 binding by pregnanolone 4.3.2. Interactions of other less active steroids with pregnanolone 89 4.4. DISCUSSION 93 4.5. CONCLUSIONS 95 Chapters 5: EFFECTS OF ^^ALPHAXALONE ON THE ENHANCEMENT BY 96 PREGNANOLONE AND ALPHAXALONE OF ^H-FLUNITRAZEPAM BINDING 5.1. INTRODUCTION 97 5.1.1. Alphaxalone and GABA^ receptors 5.1.2. A^^-alphaxalone and alphaxalone 5.1.3. Aim of this study 5.2. METHODS 100 5.3. RESULTS 100 5.3.1. Enhancement of ^H-flunitrazepam binding by A^^-alphaxalone 100 5.3.2. Effects of A^^-alphaxalone on the enhancement of 101 ^H-flunitrazepam binding by alphaxalone 5.3.3. Effects of A^^-alphaxalone on the enhancement of 102 ^H-flunitrazepam binding by pregnanolone 5.4. DISCUSSION 107 5.5. CONCLUSIONS 110 Ch^ters 6: INTERACTIONS BETWEEN LORECLEZOLE, CHLORMETHIAZOLE 111 AND PENTOBARBITONE IN MODULAHON OF ^H-FLUNITRAZEPAM BINDING TO RAT SYNAPTIC MEMBRANES 6.1. INTRODUCTION 112 6.1.1. Interactions of loreclezole and chlormethiazole with GABA^ receptors 6.1.2. Aim of this study 7 6.2. METHODS 115 6.3. RESULTS 116 6.3.1. Effects of loreclezole and chlormethiazole on ^H-flunitrazepam 116 binding 6.3.2. Effects of chlormethiazole and / or bicucuUine on the 117 enhancement by loreclezole of ^H-flunitrazepam binding 6.3.3. Enhancement by pentobarbitone of ^H-Uunitrazepam binding 118 6.4. DISCUSSION 122 6.5. CONCLUSIONS 124 Chuter 7: INTERACTIONS BETWEEN LORECLEZOLE; CHLORMETHIAZOLE 125 AND PENTOBARBITONE AT GABA^ RECEPTORS IN RAT CUNEATE NUCLEUS IN VITRO 7.1. INTRODUCTION 126 7.2. METHODS 126 7.3. RESULTS 130 7.3.1. Effects of chlormethiazole, pentobarbitone and loreclezole 130 individually 7.3.2. Effects of chlormethiazole, pentobarbitone and loreclezole 130 in pairs 7.4. DISCUSSION 135 7.5. CONCLUSIONS 136 Chapter 8: GENERAL DISCUSSION 138 8.1. MULTIPLE BINDING SITES FOR STEROIDS ON GABA^ 139 RECEPTORS 8.2. PHYSIOLOGICAL IMPLICATIONS OF STEROID 142 INTERACTIONS WITH GABA^ RECEPTORS 8.3. "MULTIPLE BINDING SITES", A COMMON FEATURE 146 FOR MODULATORS ON GABA^ RECEPTORS? 8.4. DIFFERENT PICFURES FROM BINDING AND 147 FUNCTIONAL STUDIES 8.5. FUTURE PERSPECTIVES 149 ACKNOWLEDGEMENTS 154 REFERENCES 155 LIST OF FIGURES 1.1. Essential structural features of the GABA^ receptor channel 36 1.2. The lettering of the steroid rings and numbering of the carbon atoms 38 2.1. Time profile of ^H-flunitrazepam binding 59 2.2. Time profile of the effect of DMSG on ^H-flunitrazepam binding 60 2.3. Diagram of the tissue bath, perfusion and recording system 61 used for grease-gap recordings 3.1. Structures of pregnanolone and 11-ketoprogesterone 66 3.2. Concentration-effect relationships for the enhancement of 74 ^H-fiunitrazepam binding by pregnanolone in the absence and presence of 11-ketoprogesterone 3.3. Concentration-effect relationships for the enhancement of 75 ^H-fiunitrazepam binding by propofol in the absence and presence of 11-ketoprogesterone 3.4. Concentration-effect relationships for the enhancement of 76 ^H-flunitrazepam binding by pregnanolone in the absence and presence of bicucuUine and muscknol 3.5. Concentration-effect relationships for the enhancement of 77 ^H-flunitrazepam binding by propofol in the absence and presence of bicucuUine and muscimol 4.1. The structures and synthetic pathway of some relevant steroids 86 4.2. Concentration-effect relationships for the enhancement of 90 ^H-fiunitrazepam binding by pregnanolone in the absence 10 and presence of progesterone 4.3. Concentration-efiFect relationships for the enhancement of 91 ^H-flunitrazepam binding by pregnanolone in the absence and presence of pregnenolone 4.4. Concentration-effect relationships for the enhancement of 92 ^H-flunitrazepam binding by pregnanolone in the absence and presence of epipregnanolone 5.1. Structures of alphaxalone and A'^-alphaxalone 99 5.2. Concentration-effect relationships for the enhancement of 104 ^H-flunitrazepam binding by A^^-alphaxalone in the absence and presence of bicucuUine 5.3. Concentration-effect relationships for the enhancement of 105 ^H-flunitrazepam binding by alphaxalone in the absence and presence of A^-alphaxalone 5.4. Concentration-efiFect relationships for the enhancement ofi 106 ^H-flunitrazepam binding by pregnanolone in the absence and presence ofi A^^-alphaxalone 6.1. Structures ofi loreclezole and chlormethiazole 114 6.2. Concentration-efiFect relationship for the enhancement by loreclezole 119 and the effect of chlormethiazole of ^H-flunitrazepam binding 6.3. Saturation curve and Scatchard plot for ^H-flunitrazepam binding 120 in the absence and presence of loreclezole 6.4.
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    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/04/18/jpet.116.232983.DC1 1521-0103/357/3/580–590$25.00 http://dx.doi.org/10.1124/jpet.116.232983 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 357:580–590, June 2016 Copyright ª 2016 The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Analysis of b-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives s S. Khom,1 J. Hintersteiner,2 D. Luger,2 M. Haider, G. Pototschnig, M. D. Mihovilovic, C. Schwarzer,1 and S. Hering Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (S.K., J.H., D.L., S.H.); Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria (M.H., G.P., M.D.M.); and Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (C.S.) Received February 20, 2016; accepted April 6, 2016 Downloaded from ABSTRACT Valerenic acid (VA)—a b2/3-selective GABA type A (GABAA) 40.4 6 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 6 1.8 mg/kg receptor modulator—displays anxiolytic and anticonvulsive ef- PTZ versus VA-A 3 mg/kg: 57.9 6 1.9 mg/kg PTZ, P , 0.05). fects in mice devoid of sedation, making VA an interesting drug Similarly, VA’s methylamide (VA-MA) enhancing IGABA through candidate. Here we analyzed b-subunit-dependent enhance- b3-containing receptors more efficaciously than VA (Emax 5 jpet.aspetjournals.org ment of GABA-induced chloride currents (IGABA) by a library of VA 1043 6 57%, P , 0.01, n 5 6) displayed stronger anticonvulsive derivatives and studied their effects on pentylenetetrazole (PTZ)- effects.
  • Calcium-Engaged Mechanisms of Nongenomic Action of Neurosteroids

    Calcium-Engaged Mechanisms of Nongenomic Action of Neurosteroids

    Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Rebas, Elzbieta, Tomasz Radzik, Tomasz Boczek, and Ludmila Zylinska. 2017. “Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids.” Current Neuropharmacology 15 (8): 1174-1191. doi:10.2174/1570159X15666170329091935. http:// dx.doi.org/10.2174/1570159X15666170329091935. Published Version doi:10.2174/1570159X15666170329091935 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160234 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA 1174 Send Orders for Reprints to [email protected] Current Neuropharmacology, 2017, 15, 1174-1191 REVIEW ARTICLE ISSN: 1570-159X eISSN: 1875-6190 Impact Factor: 3.365 Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids BENTHAM SCIENCE Elzbieta Rebas1, Tomasz Radzik1, Tomasz Boczek1,2 and Ludmila Zylinska1,* 1Department of Molecular Neurochemistry, Faculty of Health Sciences, Medical University of Lodz, Poland; 2Boston Children’s Hospital and Harvard Medical School, Boston, USA Abstract: Background: Neurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events.