DOCSLIB.ORG

Ongoing Challenges for the Tox Lab in Identifying Cannabinoid Receptor Agonists by Sarah Urfer, M.S., D-ABFT-FT Disclosure and Disclaimer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ongoing Challenges for the Tox Lab in Identifying Cannabinoid Receptor Agonists by Sarah Urfer, M.S., D-ABFT-FT Disclosure and Disclaimer Ongoing Challenges for the Tox Lab in Identifying Cannabinoid Receptor Agonists By Sarah Urfer, M.S., D-ABFT-FT Disclosure and Disclaimer • Disclosure • I work for and own a portion of ChemaTox Laboratory, Inc. • Disclaimer • I have no affiliation or interest in any of the other companies, brands, groups, or organizations mentioned in this presentation. All information is provided for educational purposes only. Cannabinoid Receptor Agonists AKA SYNTHETIC CANNABINOIDS Just like the Potpourri grandma has Product photos used with permission from Kevin Shanks, M.S., D-ABFT-FT From AIT Laboratories In The Beginning • Researchers synthesized 100’s, maybe 1000’s of “research chemicals” • Looking for compounds with binding affinity and activity to use as possible therapeutic drugs • John W. Huffman, Organic chemist from Clemson University • JWH-018 one of the first seen on the market 2008 - Germany • Affinity for the cannabinoid (CB1) receptor 5X greater than THC Today • Legal Highs are everywhere • “not for human consumption” • Most made in China • New ones made faster than we can: • Regulate • Test for • Characterize • 14 recognizable chemical families • 100+ new compounds a year Effects • Euphoria • Anxiety • Agitation • Paranoia • Hallucinations • Tachycardia • Hypertension • Excessive sweating • Nausea, and vomiting • Deaths have been reported Popularity • Growing since 2006 • Population dependent • Monitoring the Future Survey • http://www.drugabuse.gov/trends-statistics/monitoring- future/monitoring-future-study-trends-in-prevalence- various-drugs Monitoring the Future Study: Trends in Prevalence of Various Drugs for 8th Graders, 10th Graders, and 12th Graders; 2011 - 2014 (in percent)* Time 8th Graders 10th Graders 12th Graders Drug Period 2011 2012 2013 2014 2011 2012 2013 2014 2011 2012 2013 2014 K2/Spice [5.40 [5.80 (Synthetic Past Year - 4.4 4 3.3 - 8.8 7.4 11.4 11.3 [7.90] ] ] Marijuana) * Data in brackets indicate statistically significant change from the previous year. The Pattern • Here today, gone tomorrow • Manufacturer make new drug • Shows up on street • Law Enforcement seizures • Hospital Emergency Departments • Forensic Labs • Regulations put in place • Next day • Manufacturer make new drug A lot of variety STRUCTURES AB-CHMINACA vs THC • N-(1-Amino-3methyl-1- oxoButan-2-yl)- 1CycloHexylMethyl-1H- INdAzole-3-CarboxAmide • Δ9-TetraHydroCannabinol Make Your Own Synthetic Cannabinoid http://www.emcdda.europa.eu/topics/pods/synthetic-cannabinoids#panel2 Examples METHODS Moving Target • Many compounds • 100+ new per year • Takes time to find out what is new • Predicting new compounds? • Development - limited data • Scope • Targeted vs Untargeted • Concentrations are often single digit ng/mL • So Many Possibilities! ELISA • Fast • Prep and Run time • Low sample volume • Many labs can run them • Lags behind what is current • Need low cutoffs • Metabolites may cross react • Simple data analysis GC/MS • full scan data acquisition • Patterns can be seen for structures of the synthetic cannabinoids • Example: naphthoylindoles fragmentation patterns well studied • Comparison of the spectra with commercial and open spectral databases • Chromatography–mass spectrometry studies on the metabolism of synthetic cannabinoids JWH-018 and JWH-073, psychoactive components of smoking mixtures, Andrej Grigoryev et al. Journal of Chromatography B Volume 879, Issues 15–16, 1 May 2011, Pages 1126– 1136 LC-MS/MS • Sensitive – low limits of detection (LOD) • Low sample volume • Targeted • Chromatographic conditions – simple • Limited by available standards • Development and validation of a liquid chromatography–tandem mass spectrometry method for the quantitation of synthetic cannabinoids of the aminoalkylindole type and methanandamide in serum and its application to forensic samples, Sebastian Dresen, et al, Journal of Mass Spectrometry Volume 46, Issue 2, pages 163–171, February 2011, DOI: 10.1002/jms.1877 Q-TOF LC/MS • Detect many possible compounds • Tentative ID: parent drugs & metabolites • Instruments are expensive • Knowledge of how to analyze data • Untargeted or Targeted • Higher LODs • Comprehensive analytical strategies based on high-resolution time- of-flight mass spectrometry to identify new psychoactive substances María Ibáñez, et al, TrAC Trends in Analytical Chemistry Volume 57, May 2014, Pages 107–117 A to Z WHAT ARE WE LOOKING FOR Reference Lab – 33 compounds • 5F-AB-001 • APINACA (AKB-48) • 5F-ADB-PINACA • BB-22 • 5F-ADBICA • FUB-AKB-48 • 5F-APICA • FUB-PB-22 • 5F-APINACA (5F-AKB-48) • FUBIMINA • 5F-MN-18 • JWH-018 • 5F-PB-22 • JWH-081 • AB-CHMINACA • JWH-122 • AB-FUBINACA • JWH-210 • AB-PINACA • MDMB-CHMINACA • ADB-CHMINACA • MN-18 • ADB-FUBINACA • MN-25 • ADB-PINACA • PB-22 • ADBICA • THJ-018 • AM-2201 • THJ-2201 • APICA • UR-144 • XLR-11 Reality for Most Labs • Expensive • Time consuming • Instrument time • Instrument types • Is it worth is • A few reference labs have dedicated programs • Many labs outsource the testing Conclusions • Data, more data • Standardization • Methods • Cutoffs and LODs • Published methods • Case studies, Research - Interpretation • Faster identification of new compounds • Education and awareness • Public & Professional It’s that time again – LUNCH! References • Pharmacology, Toxicology, and Adverse Effects of Synthetic Cannabinoid Drugs ss s S. M. R. Gurney, K. S. Scott, S. L. Kacinko, B. C. Presley, B. K. Logan Forensic Science Review 26:53; 01/2014 • http://www.cpdd.org/Pages/Links/Links_PDFs/SyntheticDrugofAbuseUpdateJune2014.pdf %20FINAL.pdf • Comprehensive review of the detection methods for synthetic cannabinoids and cathinones Akira Namera,corresponding author Maho Kawamura, Akihiro Nakamoto, Takeshi Saito, and Masataka Naga, Forensic Toxicol. 2015; 33(2): 175–194. Published online 2015 Mar 6. doi: 10.1007/s11419-015-0270-0 PMCID: PMC4525208 • Synthetic cannabinoid use among patients in residential substance use disorder treatment: prevalence, motives, and correlates. Bonar EE, Ashrafioun L, Ilgen MA, Drug Alcohol Depend. 2014 Oct 1;143:268-71. doi: 10.1016/j.drugalcdep.2014.07.009. Epub 2014 Jul 17 • Zaitsu K, Katagi M, Nakanishi K, Shima N, Kamata H, Kamata T, Nishioka H, Miki A, Tatsuno M, Iwamura T, Sato T, Tsuchihashi H, Suzuki K. Comprehensive analytical methods of the synthetic cannabinoids appearing in the illicit drug market (in Japanese with English abstract) Jpn J Forensic Sci Tech. 2011;16:73–90..
Load more

Recommended publications
  • Recommended Methods for the Identification and Analysis of Synthetic Cannabinoid Receptor Agonists in Seized Materials (Revised and Updated)
    Recommended methods for the Identification and Analysis of Synthetic Cannabinoid Receptor Agonists in Seized Materials (Revised and updated) MANUAL FOR USE BY NATIONAL DRUG ANALYSIS LABORATORIES Photo credits: UNODC Photo Library; UNODC/Ioulia Kondratovitch; Alessandro Scotti. Laboratory and Scientific Section UNITED NATIONS OFFICE ON DRUGS AND CRIME Vienna Recommended Methods for the Identification and Analysis of Synthetic Cannabinoid Receptor Agonists in Seized Materials (Revised and updated) MANUAL FOR USE BY NATIONAL DRUG ANALYSIS LABORATORIES UNITED NATIONS Vienna, 2020 Note Operating and experimental conditions are reproduced from the original reference materials, including unpublished methods, validated and used in selected national laboratories as per the list of references. A number of alternative conditions and substitution of named commercial products may provide comparable results in many cases, but any modification has to be validated before it is integrated into laboratory routines. Mention of names of firms and commercial products does not imply theendorsement of the United Nations. ST/NAR/48/REV.1 © United Nations, July 2020. All rights reserved, worldwide The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. This publication has not been formally edited. Publishing production: English, Publishing and Library Section, United Nations Office at Vienna. Acknowledgements The Laboratory and Scientific Services of the United Nations Office on Drugs and Crime (UNODC) (LSS, headed by Dr.
    [Show full text]
  • Model Scheduling New/Novel Psychoactive Substances Act (Third Edition)
    Model Scheduling New/Novel Psychoactive Substances Act (Third Edition) July 1, 2019. This project was supported by Grant No. G1799ONDCP03A, awarded by the Office of National Drug Control Policy. Points of view or opinions in this document are those of the author and do not necessarily represent the official position or policies of the Office of National Drug Control Policy or the United States Government. © 2019 NATIONAL ALLIANCE FOR MODEL STATE DRUG LAWS. This document may be reproduced for non-commercial purposes with full attribution to the National Alliance for Model State Drug Laws. Please contact NAMSDL at [email protected] or (703) 229-4954 with any questions about the Model Language. This document is intended for educational purposes only and does not constitute legal advice or opinion. Headquarters Office: NATIONAL ALLIANCE FOR MODEL STATE DRUG 1 LAWS, 1335 North Front Street, First Floor, Harrisburg, PA, 17102-2629. Model Scheduling New/Novel Psychoactive Substances Act (Third Edition)1 Table of Contents 3 Policy Statement and Background 5 Highlights 6 Section I – Short Title 6 Section II – Purpose 6 Section III – Synthetic Cannabinoids 13 Section IV – Substituted Cathinones 19 Section V – Substituted Phenethylamines 23 Section VI – N-benzyl Phenethylamine Compounds 25 Section VII – Substituted Tryptamines 28 Section VIII – Substituted Phenylcyclohexylamines 30 Section IX – Fentanyl Derivatives 39 Section X – Unclassified NPS 43 Appendix 1 Second edition published in September 2018; first edition published in 2014. Content in red bold first added in third edition. © 2019 NATIONAL ALLIANCE FOR MODEL STATE DRUG LAWS. This document may be reproduced for non-commercial purposes with full attribution to the National Alliance for Model State Drug Laws.
    [Show full text]
  • Appendix-2Final.Pdf 663.7 KB
    North West ‘Through the Gate Substance Misuse Services’ Drug Testing Project Appendix 2 – Analytical methodologies Overview Urine samples were analysed using three methodologies. The first methodology (General Screen) was designed to cover a wide range of analytes (drugs) and was used for all analytes other than the synthetic cannabinoid receptor agonists (SCRAs). The analyte coverage included a broad range of commonly prescribed drugs including over the counter medications, commonly misused drugs and metabolites of many of the compounds too. This approach provided a very powerful drug screening tool to investigate drug use/misuse before and whilst in prison. The second methodology (SCRA Screen) was specifically designed for SCRAs and targets only those compounds. This was a very sensitive methodology with a method capability of sub 100pg/ml for over 600 SCRAs and their metabolites. Both methodologies utilised full scan high resolution accurate mass LCMS technologies that allowed a non-targeted approach to data acquisition and the ability to retrospectively review data. The non-targeted approach to data acquisition effectively means that the analyte coverage of the data acquisition was unlimited. The only limiting factors were related to the chemical nature of the analyte being looked for. The analyte must extract in the sample preparation process; it must chromatograph and it must ionise under the conditions used by the mass spectrometer interface. The final limiting factor was presence in the data processing database. The subsequent study of negative MDT samples across the North West and London and the South East used a GCMS methodology for anabolic steroids in addition to the General and SCRA screens.
    [Show full text]
  • JWH-073 Critical Review Report Agenda Item 4.11
    JWH-073 Critical Review Report Agenda item 4.11 Expert Committee on Drug Dependence Thirty-eight Meeting Geneva, 14-18 November 2016 38th ECDD (2016) Agenda item 4.11 JWH-073 Page 2 of 29 38th ECDD (2016) Agenda item 4.11 JWH-073 Contents Acknowledgements ................................................................................................................... 5 Summary ................................................................................................................................... 6 1. Substance identification .................................................................................................... 7 A. International Nonproprietary Name (INN) .................................................................. 7 B. Chemical Abstract Service (CAS) Registry Number .................................................. 7 C. Other Chemical Names ................................................................................................ 7 D. Trade Names ................................................................................................................ 7 E. Street Names ................................................................................................................ 7 F. Physical Appearance .................................................................................................... 7 G. WHO Review History ................................................................................................. 7 2. Chemistry ..........................................................................................................................
    [Show full text]
  • Suspected Synthetic Cannabinoid Receptor Agonist Intoxication: Does
    American Journal of Emergency Medicine 37 (2019) 1846–1849 Contents lists available at ScienceDirect American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem Original Contribution Suspected synthetic cannabinoid receptor agonist intoxication: Does analysis of samples reflect the presence of suspected agents? ⇑ Collin Tebo a, Maryann Mazer-Amirshahi PharmD, MD, MPH a,b, , Lindsey DeGeorge, MD b, Bradley Gelfand a, Chikarlo Leak, DrPH, MPH c, Samantha Tolliver, PhD c, Diane Sauter, MD, MS a,b a Georgetown University School of Medicine, Washington, DC, United States of America b Department of Emergency Medicine, MedStar Washington Hospital Center, Washington, DC, United States of America c Office of the Chief Medical Examiner, Washington, DC, United States of America article info abstract Article history: Background: There has been a surge in synthetic cannabinoid receptor agonist (SCRA) exposures reported Received 15 November 2018 in recent years. The constituents of SCRA preparations are constantly evolving and rarely confirmed. Received in revised form 20 December 2018 We sought to characterize the constituents of reported SCRA exposures presenting to the emergency Accepted 23 December 2018 department (ED). Methods: Patients who presented to two academic EDs in Washington, DC with reported or suspected SCRA exposure from July 2015–July 2016 were enrolled at the discretion of the treating provider. Keywords: Blood and/or urine samples were obtained as part of routine clinical care and sent to the DC medical Synthetic cannabinoids examiner’s office for identification of known SCRAs with liquid chromatography-mass spectrometry- Synthetic cannabinoid receptor agonists Suspected intoxication mass spectrometry. Standard toxicology screens were additionally performed to determine the presence New psychoactive substances of other drugs of abuse.
    [Show full text]
  • Alcohol and Drug Abuse Subchapter 9 Regulated Drug Rule 1.0 Authority
    Chapter 8 – Alcohol and Drug Abuse Subchapter 9 Regulated Drug Rule 1.0 Authority This rule is established under the authority of 18 V.S.A. §§ 4201 and 4202 which authorizes the Vermont Board of Health to designate regulated drugs for the protection of public health and safety. 2.0 Purpose This rule designates drugs and other chemical substances that are illegal or judged to be potentially fatal or harmful for human consumption unless prescribed and dispensed by a professional licensed to prescribe or dispense them, and used in accordance with the prescription. The rule restricts the possession of certain drugs above a specified quantity. The rule also establishes benchmark unlawful dosages for certain drugs to provide a baseline for use by prosecutors to seek enhanced penalties for possession of higher quantities of the drug in accordance with multipliers found at 18 V.S.A. § 4234. 3.0 Definitions 3.1 “Analog” means one of a group of chemical components similar in structure but different with respect to elemental composition. It can differ in one or more atoms, functional groups or substructures, which are replaced with other atoms, groups or substructures. 3.2 “Benchmark Unlawful Dosage” means the quantity of a drug commonly consumed over a twenty-four hour period for any therapeutic purpose, as established by the manufacturer of the drug. Benchmark Unlawful dosage is not a medical or pharmacologic concept with any implication for medical practice. Instead, it is a legal concept established only for the purpose of calculating penalties for improper sale, possession, or dispensing of drugs pursuant to 18 V.S.A.
    [Show full text]
  • Metabolism of MMB022 and Identification of Dihydrodiol Formation in Vitro Using Synthesized Standards
    Received: 5 April 2020 Revised: 23 June 2020 Accepted: 24 June 2020 DOI: 10.1002/dta.2888 RESEARCH ARTICLE Metabolism of MMB022 and identification of dihydrodiol formation in vitro using synthesized standards Shimpei Watanabe1,2 | Xiongyu Wu3 | Johan Dahlen3 | Peter Konradsson3 | Svante Vikingsson1,2 | Robert Kronstrand1,2 | Henrik Gréen1,2 1Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping Abstract University, Linköping, Sweden MMB022 (methyl 3-methyl-2-[1-(pent-4-en-1-yl)-1H-indole-3-carboxamido]but- 2 Department of Forensic Genetics and anoate) is a new synthetic cannabinoid with an alkene at the pentenyl side chain, a Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden rare functional group for synthetic cannabinoids. Metabolite identification is an 3Department of Physics, Chemistry and important step for the detection of synthetic cannabinoids in humans, since they are Biology, Linköping University, Linköping, Sweden generally extensively metabolized. The aims of the study were to tentatively identify in vitro phase I metabolites, to confirm major metabolites using synthesized metabo- Correspondence Henrik Gréen and Shimpei Watanabe, Division lites, to examine metabolic pathways thoroughly, to study metabolic stability and to of Drug Research, Department of Biomedical suggest metabolites appropriate for urine screening. MMB022 and its synthesized and Clinical Sciences, Linköping University, 581 85. Linköping Sweden. metabolites were incubated with human liver microsomes (HLM) and the superna- Email: [email protected]; shimpei. tants were analyzed by liquid chromatography-quadrupole time-of-flight mass spec- [email protected] trometry. Sixteen metabolites were identified, which were generated via Funding information dehydrogenation, dihydrodiol formation, ester hydrolysis, hydroxylation, and combi- Eurostars-2 Joint programme, Grant/Award Number: E! 113377, NPS-REFORM; Strategic nations thereof.
    [Show full text]
  • ARK™ AB-PINACA Assay
    3 SUMMARY AND EXPLANATION OF THE TEST Synthetic cannabinoids are part of a group of drugs called new psychoactive substances (NPS), which are designer drugs intended to mimic the effects of illicit drugs. These substances are called cannabinoids because they interact with the same CB1 and CB2 cannabinoid receptors as tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. For Export Only – Not For Sale in USA Although synthetic cannabinoids are functionally similar to THC, many of these substances are not structurally related to THC. Synthetic cannabinoids became popular under the brand names “Spice” and “K2”, in part due to their ability to escape detection by standard cannabinoid screening tests. Synthetic cannabinoids are marketed under a wide variety of specific brand ™ ARK AB-PINACA Assay names, including Joker, Black Mamba, Kush, and Kronic. Synthetic cannabinoids are used This ARK Diagnostics, Inc. package insert for the ARK AB-PINACA Assay must be read prior in a variety of ways, with the most common method being sprayed onto dried plant material to use. Package insert instructions must be followed accordingly. The assay provides a simple and smoked. Potential adverse effects of synthetic cannabinoid use include anxiety, agitation, and rapid analytical screening procedure for detecting AB-PINACA and its metabolites in hallucinations, dizziness, seizures, rapid heart rate and vomiting.1-9 urine. Reliability of the assay results cannot be guaranteed if there are any deviations from the 4 PRINCIPLES OF THE PROCEDURE instructions in this package insert. The ARK AB-PINACA Assay is a homogeneous enzyme immunoassay method used for the analysis of drug in human urine.
    [Show full text]
  • Modified Test Updates
    Effective Date: Monday, February 27, 2017 Test Updates Immediate Action - Modified Updated January 24, 2017: Added test codes 1486B, 1486SP, 1485B and 1485SP. In our continuing effort to provide you with the highest quality toxicology laboratory services available, we have compiled important changes regarding a number of tests we perform. Listed below are the types of changes that may be included in this notification, effective Monday, February 27, 2017 Test Changes - Tests that have had changes to the method/ CPT code, units of measurement, scope of analysis, reference comments, or specimen requirements. Discontinued Tests - Tests being discontinued with alternate testing suggestions. Please use this information to update your computer systems/records. These changes are important to ensure standardization of our mutual laboratory databases. If you have any questions about the information contained in this notification, please call our Client Support Department at (866) 522-2206. Thank you for your continued support of NMS Labs and your assistance in implementing these changes. The CPT Codes provided in this document are based on AMA guidelines and are for informational purposes only. NMS Labs does not assume responsibility for billing errors due to reliance on the CPT Codes listed in this document. NMS LABS 3701 Welsh Road Willow Grove, PA 19090 www.NMSLabs.com Page 1 of 12 Effective Date: Monday, February 27, 2017 Test Updates Test Test Name Test Method / Specimen Stability Scope Units Reference Discontinue Code Name CPT Code Req. Comments
    [Show full text]
  • Overdoseteamet Trondheim Kommune
    HELSETEAMET/ OVERDOSETEAMET TRONDHEIM KOMMUNE Lavterskelsamling Oslo 2017 John-Petter S. Jamt 2017 Fentanyl ● Relativt billig ● Blandes med heroin og andre illegale rusmidler ● Kommer fra Kina og Mexico (til USA) ● Distribueres via det mørke nettet (spesielt fra Kina iflg DEA) ● 4 Overdoser i Trondheim på Fentanyl (kjent av Helse- og Overdoseteamet) ● 1 dødsfall (Ortofluorofentanyl) ● Rigid ChestWall Syndrome ● 45s Tidsvindu - respirasjonsstans ● 3-6ggr dose med Nalokson - 25% av OD mer enn 5min på oppvåkning John-Petter S. Jamt 2017 Fentanyl ● Syntetisert i 1959 ● Flere typer med årene; Orto-fluoro-, para-fluoro-, Acetyl-, Butyryl-, Furanyl-, Car-, Al-, Remi- og kanskje farligst og nyest(?) Akrylfentanyl som er naloksonresistent!!! (Tetrahydrofur(an)(eon)). ● Lipidbasert ● Hurtig(!)virkende ● Relativt raskt nedbrutt/metabolisert til Norfentanyl med halveringstid ca. 8 timer. ● I lovlig form som; ● Sugetabletter ● Sublingualtabletter ● Plaster - Durogesic og Fentanyl “Hexal” John-Petter S. Jamt 2017 ● China Girl ● China White (H+F) ● Apache ● Dance Fever ● Goodfella ● Murder 8 ● TNT (H+F) ● Jackpot ● Tango and Cash ● Great Bear ● He-Man ● Jackpot ● King Ivory ● Murder 8 ● Poison (H+F) ● Perc-a-Pop John-Petter S. Jamt 2017 NPS - Nye Psykoaktive Substanser Sammendrag/Fellestrekk De fleste NPS virker stimulerende på hjernen ● Økt våkenhet og utholdenhet ● Hevet stemningsleie ● Bedre selvfølelse ● Nedsatt kritisk sans Mange er hallusinogene med ● Sansebedrag ● Illusjoner ● Hallusinasjoner John-Petter S. Jamt 2017 NPS - Nye Psykoaktive Substanser Inndeling i flere typer; ❖ Syntetiske cannabinoider ➢ Lignende virkning som THC - I hovedsak på cannabinoidreseptorer. ➢ Betydelig mer potente ■ Større risiko for psykose, kramper, koma ■ kardiovaskulære bivirkninger ➢ Redusert kritisk sans ➢ Økt aggresjon ➢ Psykoser, angst ■ ulykker, selvmord og voldsepisoder ➢ Forgiftningsdødsfall (MDMB-CHMICA (på Steinkjer)) ➢ K2 (i USA) ❖ En hel “skog” av forskjellige typer cannabinoider…… HOLD FAST!! John-Petter S.
    [Show full text]
  • Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids
    JPET Fast Forward. Published on March 16, 2018 as DOI: 10.1124/jpet.117.246983 This article has not been copyedited and formatted. The final version may differ from this version. JPET #246983 Molecular and behavioral pharmacological characterization of abused synthetic cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-fluoro-CUMYL-PICA Thomas F. Gamage, Charlotte E. Farquhar, Timothy W. Lefever, Julie A. Marusich, Richard C. Kevin, Iain S. McGregor, Jenny L. Wiley, and Brian F. Thomas RTI International, Research Triangle Park, NC. Downloaded from jpet.aspetjournals.org at ASPET Journals on September 24, 2021 1 JPET Fast Forward. Published on March 16, 2018 as DOI: 10.1124/jpet.117.246983 This article has not been copyedited and formatted. The final version may differ from this version. JPET #246983 Running Title: Pharmacological characterization of synthetic cannabinoids Brian F. Thomas 3040 Cornwallis Rd. Research Triangle Park, NC. 27709 919-541-6552 Downloaded from [email protected] Number of pages: 39 jpet.aspetjournals.org Number of tables: 4 Number of figures: 5 at ASPET Journals on September 24, 2021 Number of references: 62 Abstract word count: 250 Introduction word count: 745 Discussion word count: 1495 Nonstandard abbreviations: human cannabinoid type-1 receptor, hCB1, human cannabinoid type- 2 receptor, hCB2, dimethyl sulfoxide, DMSO; bovine serum albumin, BSA; human embryonic kidney-293 cells, HEK293; Chinese hamster ovary cells, CHO; 3-Isobutyl-1-methylxanthine, IBMX; phosphate buffered saline, PBS; Section: Neuropharmacology 2 JPET Fast Forward. Published on March 16, 2018 as DOI: 10.1124/jpet.117.246983 This article has not been copyedited and formatted.
    [Show full text]
  • Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling
    International Journal of Molecular Sciences Review Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling Kenneth B. Walsh * and Haley K. Andersen Department of Pharmacology, Physiology & Neuroscience, University of South Carolina, School of Medicine, Columbia, SC 29208, USA; [email protected] * Correspondence: [email protected] Received: 24 July 2020; Accepted: 14 August 2020; Published: 25 August 2020 Abstract: Synthetic cannabinoids (SCs) are a class of new psychoactive substances (NPSs) that exhibit high affinity binding to the cannabinoid CB1 and CB2 receptors and display a pharmacological profile similar to the phytocannabinoid (-)-trans-D9-tetrahydrocannabinol (THC). SCs are marketed under brand names such as K2 and Spice and are popular drugs of abuse among male teenagers and young adults. Since their introduction in the early 2000s, SCs have grown in number and evolved in structural diversity to evade forensic detection and drug scheduling. In addition to their desirable euphoric and antinociceptive effects, SCs can cause severe toxicity including seizures, respiratory depression, cardiac arrhythmias, stroke and psychosis. Binding of SCs to the CB1 receptor, expressed in the central and peripheral nervous systems, stimulates pertussis toxin-sensitive G proteins (Gi/Go) resulting in the inhibition of adenylyl cyclase, a decreased opening of N-type Ca2+ channels and the activation of G protein-gated inward rectifier (GIRK) channels. This combination of signaling effects dampens neuronal activity in both CNS excitatory and inhibitory pathways by decreasing action potential formation and neurotransmitter release. Despite this knowledge, the relationship between the chemical structure of the SCs and their CB1 receptor-mediated molecular actions is not well understood.
    [Show full text]