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Activity-Based Detection of New Psychoactive Substances As an Alternative Screening Approach in Forensic Toxicology

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Activity-Based Detection of New Psychoactive Substances As an Alternative Screening Approach in Forensic Toxicology Activity-based detection of new psychoactive substances as an alternative screening approach in forensic toxicology. Annelies CANNAERT 2018 Promotors: Prof. Dr. Christophe Stove & Dr. Sarah Wille Thesis submitted to obtain the degree of Doctor in Pharmaceutical Sciences Copyright The author and promoters give authorization to consult and copy parts of this thesis for personal use only. Any other use is limited by the laws of copyright, especially concerning the obligation to refer to the source whenever results are cited from this thesis. De auteur en promotoren geven de toelating dit proefschrift voor consultatie beschikbaar te stellen en delen ervan te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperkingen van het auteursrecht, in het bijzonder met betrekking tot de verplichting uitdrukkelijk de bron te vermelden bij het aanhalen van resultaten uit dit proefschrift. Ghent, 2018, The promoters, Prof. Dr. Christophe Stove Dr. Sarah Wille The author, Annelies Cannaert III IV Dankwoord Na 5.5 jaar komt er een einde aan mijn doctoraatsavontuur. Tijd om even terug te kijken en enkele mensen te bedanken die direct of indirect hebben bijgedragen tot het slagen van dit project. Eerst en vooral wil ik mijn promotor prof. Christophe Stove en prof. Willy Lambert bedanken. Zonder hen kon ik uiteraard nooit starten aan mijn doctoraat. Jullie constructieve feedback heeft in belangrijke mate bijgedragen tot het realiseren van dit werk. Bedankt Christophe om het vele schrijfwerk telkens opnieuw kritisch te bekijken en telkens weer te blijven verbeteren. Ik wil je ook bedanken om me de kans te geven om mijn werk te presenteren in het buitenland. Bedankt prof. Lambert voor de goede raad, steun en leuke gesprekken op het labo en vooral tijdens/onderweg naar congressen. Vervolgens wil ik ook graag mijn tweede promotor dr. Sarah Wille bedanken. Dankzij jouw voorstel om een nieuw project in te dienen, kon ik mijn doctoraat mooi afsluiten! Ik kende je nog niet zo goed bij de project aanvraag maar dat veranderde snel in Brisbane. Ik zag al snel dat we het goed konden vinden en het was een plezier om samen te werken. Graag wil ik ook alle leden van de examencommissie bedanken om tijd te nemen dit werk te lezen en grondig te bediscussiëren. Bedankt aan alle collega’s waarmee ik heb samengewerkt. Jullie hebben er allemaal op een of andere manier voor gezorgd dat dit werk tot stand kwam. Ann-Sofie, Filip, Jeroen, Pieter, Nele, Valerie, Ann en Goedele, jullie waren er al vanaf het begin. In de eerste jaren moest ik nog veel uitzoeken en ging het allemaal niet zo vlotjes, maar jullie waren er altijd om es mijn gedachten te kunnen verzetten! Sofie, Sara, Phebe en Rani, ondanks dat we geheel verschillende onderwerpen hebben, kon ik altijd bij jullie terecht met allerlei vragen, bedenkingen en leuke pauze momentjes. Lars, bijna al mijn buitenlandse congressen waren samen met jou. Bedankt om mij, als nieuweling, te introduceren aan allerlei mensen. We hebben samen veel plezier gehad, zowel tijdens als naast de congressen! Lisa en Jana, jullie steun tijdens de laatste fase van mijn doctoraat is niet te onderschatten. Aangezien schrijven alleen thuis niet mijn sterkste kant is, was het heel plezant om tijdens de kerstvakantie en sommige weekends toch nog mensen rond mij te hebben die ook bezig waren. Elly, Elke, Linde, Katleen, Elise, Kamila, René, Ming, Lakshmi, Kathleen, Eline en Aurelie: jullie komst bracht een frisse wind in het labo. Alles werd een beetje krapper/gezelliger . Maar eindelijk hadden Jolien en ik cel/bureau-vriendjes V Florian, Cornelius, Melissa and Mandi, without your collaboration this book would not exist! I do not know how many emails were sent for this thesis, but in the end it resulted in nice publications, where we all can be proud of . Een extra grote bedanking gaat uit naar Jolien, mijn cel-partner in crime van in het begin. Samen hebben we vaak onze cellen en klonering reacties vervloekt. Maar er is niemand die kan begrijpen hoe je uitzinnig kan zijn van vreugde als je uiteindelijk een bandje ziet bij een kloneringsreactie waaraan je al maanden bezig bent (alhoewel Eline zich daar ondertussen ook kan in inleven ;) ) Verder moet ik mijn vrienden ook bedanken. Ik heb jullie de laatste maanden heel wat minder gezien dan dat ik wou, maar ik beloof dat ik dat snel weer goed ga maken! En indien er nog eens een (buitenlands) tripje gemaakt wordt, ben ik er sowieso bij . Ik wil ook nog mijn lacrosse team bedanken. Tijdens de lacrosse trainingen kon ik mijn energie (en soms frustraties) helemaal kwijt raken. Maar ook naast de trainingen en wedstrijden waren jullie daar voor mij! Ten slotte wil ik nog heel graag mijn ouders en broer bedanken voor de steun tijdens mijn studies en doctoraat en nog zoveel meer. Jullie hebben me de kans en vrijheid gegeven om mijn eigen weg te volgen, waarbij ik steeds op jullie kon rekenen. VI Table of Contents List of abbreviations XI CHAPTER 1: AIMS AND OUTLINE OF THE THESIS 1 1.1 Introduction to new psychoactive substances 3 1.1.1 Synthetic cannabinoids 4 1.1.2 Synthetic opioids 7 1.2 Outline and aims of the thesis 10 1.3 References 11 CHAPTER 2: ACTIVITY-BASED REPORTER ASSAYS FOR THE SCREENING OF ABUSED SUBSTANCES IN BIOLOGICAL MATRICES: AN OVERVIEW 15 2.1 Introduction 17 2.2 Ideal in vitro activity-based assay 19 2.3 New psychoactive substances: synthetic cannabinoids and opioids 19 2.4 Steroid hormones 22 2.4.1 Receptor binding assays 24 2.4.2 Cell proliferation assays 24 2.4.3 Reporter gene bioassays 25 - Yeast 25 - Mammalian cells 30 2.5 Concluding remarks 32 2.6 References 35 CHAPTER 3: DETECTION AND ACTIVITY PROFILING OF SYNTHETIC CANNABINOID RECEPTOR AGONISTS AND THEIR METABOLITES WITH A NEWLY DEVELOPED BIOASSAY 43 3.1 Introduction 45 3.2 Materials and Methods 48 3.2.1 Chemicals and Reagents 48 3.2.2 Plasmids and Constructs 48 3.2.3 Cell culture and Transfection 50 3.2.4 Cannabinoid Reporter Assay 50 3.2.5 Statistical Analysis 51 3.2.6 Urine Sample Preparation 52 3.2.7 LC-ESI-MS/MS Analysis of Urine Samples 52 3.3 Results and Discussion 54 3.3.1 Design of the Cannabinoid Reporter Assay 54 3.3.2 Concentration Dependence of the Cannabinoid Reporter Assays 55 3.3.3 Application of the CB Reporter Assays on SCRAs and Their Main Phase I Metabolites 56 - JWH-018 56 - JWH-122, JWH-210, MAM-2201, and EAM-2201 60 - PB-22 and 5F-PB-22 61 3.3.4 Application of the CB Reporter Assays on Natural Cannabinoids (Δ9THC and CBD) and 63 the Main Phase I Metabolites of Δ9THC 3.3.5 Application of the CB Reporter Assay as a First-Line Screening Tool in Urine: Proof of 64 Concept 3.4 Conclusion 66 3.5 References 68 VII CHAPTER 4: ACTIVITY-BASED DETECTION OF CONSUMPTION OF SYNTHETIC CANNABINOID RECEPTOR AGONISTS IN AUTHETIC URINE SAMPLES USING A STABLE CANNABINOID REPORTER SYSTEM 75 4.1 Introduction 77 4.2 Material and Methods 79 4.2.1 Chemicals and Reagents 79 4.2.2 Retroviral Constructs 80 4.2.3 Production of Retrovirus and Retroviral Transduction 81 4.2.4 Cell Sorting and Cell Culture 81 4.2.5 Cannabinoid Reporter Assay 82 4.2.6 Statistical Analysis 82 4.2.7 Urine Sample Preparation 83 4.2.8 LC-ESI-MS/MS Analysis of Urine Samples 83 4.3 Results and Discussion 85 4.3.1 Stable Expression of the Cannabinoid Reporter Assay 85 4.3.2 Application of the CB Reporter Assays on SCRAs and Their Main Phase I Metabolites 88 - UR-144 and XLR-11 88 - AB-CHMINACA and ADB-CHMINACA 91 4.3.3 Application of the CB Reporter Assays on authentic urine samples from SCRA users 92 4.4 Conclusion 97 4.5 References 99 4.6 Addendum 103 CHAPTER 5: AN IMPROVED ACTIVITY-BASED DETECTION METHOD OF CANNABINOIDS IN SERUM AND PLASMA 107 5.1 Introduction 109 5.2 Material and Methods 110 5.2.1 Chemicals and Reagents 110 5.2.2 Plasmids and Constructs 110 5.2.3 Cell Culture and Cannabinoid Reporter Assay 112 5.2.4 Urine Sample Preparation and Analysis 113 5.2.5 Serum and Plasma Sample Preparation 113 5.2.6 Analysis of Serum Samples 113 5.2.7 Analysis of Plasma Samples 113 5.2.8 Statistical Analysis 114 5.3 Results 114 5.3.1 Development of bioassays with improved sensitivity by using truncated βarr2 forms 114 5.3.2 Application of CB bioassays with truncated βarr2 forms on batch of authentic urine 116 samples 5.3.3 Application of CB bioassays with truncated βarr2 forms on batches of authentic 118 serum and plasma samples 5.4 Discussion 123 5.5 References 127 5.6 Addendum 129 VIII CHAPTER 6: A NOVEL ACTIVITY-BASED CONCEPT TO SCREEN BIOLOGICAL MATRICES FOR THE PRESENCE OF OPIATES AND (SYNTHETIC) OPIOIDS 135 6.1 Introduction 137 6.2 Material and Methods 138 6.2.1 Chemicals and Reagents 138 6.2.2 Plasmids and Constructs 139 6.2.3 Cell Culture and MOR Reporter Assay 140 6.2.4 Statistical Analysis 140 6.2.5 Blood Sample Preparation and Analysis 140 6.3 Results 141 6.3.1 Design of the MOR Reporter Assay 141 6.3.2 G-protein coupled receptor kinase confers increased sensitivity to the MOR Reporter 142 Assay 6.3.3 Application of the MOR Reporter Assay on different opioids 143 6.3.4 Application of the MOR Reporter Assay on authentic blood samples 144 6.4 Conclusion 148 6.5 References 150 CHAPTER 7: ACTIVITY-BASED DETECTION AND BIOANALYTICAL CONFIRMATION OF A FATAL CARFENTANIL INTOXICATION 153 7.1 Introduction 155 7.2 Case Presentation 155 7.3 Discussion 159 7.4 References 160 CHAPTER 8: BROADER INTERNATIONAL CONTEXT, RELEVANCE AND FUTURE PERSPECTIVES 163 CHAPTER 9: CONCLUSION AND SUMMARY 177 SAMENVATTING 181 CURRICULUM VITAE 185 IX List of abbreviations 4-ANPP despropionyl fentanyl 5F-ADB N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-3-methyl-D-valine,
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