DOCSLIB.ORG

( 12 ) United States Patent

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
( 12 ) United States Patent US010669248B2 (12 ) United States Patent ( 10 ) Patent No.: US 10,669,248 B2 Thomas et al. (45 ) Date of Patent : Jun . 2 , 2020 (54 ) METHODS TO CHEMICALLY MODIFY 10,195,159 B2 2/2019 Whittle et al. CANNABINOIDS 10,238,705 B2 3/2019 Speier 2004/0147767 Al 7/2004 Whittle et al . 2005/0042172 A1 2/2005 Whittle ( 71) Applicant: Natural Extraction Systems, LLC , 2009/0054711 A1 2/2009 Lawrence et al. Boulder , CO (US ) 2012/0157719 Al 6/2012 Teles et al . 2016/0038437 A1 2/2016 Whittle et al. (72 ) Inventors : C. Russell Thomas, Boulder , CO (US ) ; 2018/0078874 A1 3/2018 Thomas Matthew M.DePalo , Broomfield , CO 2018/0296617 Al 10/2018 Rivas (US ) 2019/0151171 Al 5/2019 Johnson et al. ( 73 ) Assignee : Natural Extraction Systems, LLC , FOREIGN PATENT DOCUMENTS Boulder, CO (US ) CA 2472561 A1 * 8/2002 C07D 311/80 EP 3453397 A1 3/2019 ( * ) Notice: Subject to any disclaimer , the term of this JP 4849578 B1 1/2012 patent is extended or adjusted under 35 WO WO - 2002 /089945 A2 11/2002 WO WO - 2015 /049585 A2 4/2015 U.S.C. 154 ( b ) by 0 days . WO WO - 2016153347 Al * 9/2016 C07C 37/004 WO WO - 2016 / 161420 Al 10/2016 ( 21) Appl. No .: 16 /271,782 WO WO - 2017 / 192527 A1 11/2017 WO WO - 2018009514 Al * 1/2018 BO1D 3/10 ( 22 ) Filed : Feb. 9 , 2019 WO WO - 2018 / 102711 A1 6/2018 (65 ) Prior Publication Data OTHER PUBLICATIONS US 2020/0048214 A1 Feb. 13 , 2020 U.S. Appl . No. 16 / 271,783 , Thomas . U.S. Appl. No. 16 /271,820 , Thomas. Related U.S. Application Data International Search Report and Written Opinion for International (60 ) Provisional application No. 62 /717,235 , filed on Aug. Application No. PCT /US2019 /045992 dated Oct. 18 , 2019 . 10 , 2018, provisional application No. 62/ 803,408 , International Search Report and Written Opinion for International filed on Feb. 8 , 2019 . Application No. PCT /US2019 / 045950 dated Nov. 15 , 2019 . Kanter et al. , “ Quantitative determination of detla9 -tetrahydrocan nabinol and delta9 - tretrahydro - cannabinolic acid in marihuana by (51 ) Int. Ci. high - pressure liquid chromatography, ” J Chromatogr 171: 504-508 CO7D 311/78 ( 2006.01 ) ( 1979 ) . C07C 29/80 (2006.01 ) Veress et al. , “ Determination of cannabinoid acids by high C07C 67/08 (2006.01 ) performance liquid chromatography of their neutral derivatives BOID 5/00 ( 2006.01 ) formed by thermal decarboxylation : I. Study of the decarboxylation (52 ) U.S. CI. process in open reactors ,” J Chromatogr, 520 :339-347 ( 1990 ). CPC CO7D 311/78 (2013.01 ) ; C07C 29/80 ( 2013.01) ; C07C 67/08 ( 2013.01 ) ; B01D 5/006 * cited by examiner (2013.01 ) (58 ) Field of Classification Search Primary Examiner Noble E Jarrell CPC CO7D 311/78 ; C07C 29/80 ; BO1D 5/006 ( 74 ) Attorney, Agent, or Firm - Douglas G. Metcalf See application file for complete search history. (57 ) ABSTRACT (56 ) References Cited Various aspects of this disclosure relate to methods to lower the activation energy of the cannabinoid decarboxylation U.S. PATENT DOCUMENTS reaction by performing the decarboxylation reaction in the 4,396,487 A 8/1983 Strumskis gas phase . 9,987,567 B1 * 6/2018 Ko C07C 37/004 10,159,908 B2 12/2018 Thomas 15 Claims, 4 Drawing Sheets U.S. Patent Jun . 2 , 2020 Sheet 1 of 4 US 10,669,248 B2 Fig. 1 OH a H j. H " i H b d H? ?. ? ZoCOV H g HO locom OH b Coa H H jo--- M2 H io SH Ia H 8t H H g h ?? U.S. Patent Jun . 2 , 2020 Sheet 2 of 4 US 10,669,248 B2 Fig. 2 a h ON U.S. Patent Jun . 2 , 2020 Sheet 3 of 4 US 10,669,248 B2 Fig . 3 Representative Cannabinoid Concentrations in USDA Organic IndustrialHemp 12 % 10 % 8 % 6 % 4 % 2 % 0 % THCA THC CBDA CBD CBN CBG Fig . 4 Representative Cannabinoid Concentrations in Concentrate Produced from Liquid Distillate 70 % 60 % 50 % 40 % 30 % 20 % 10 % 0 % THCA THC CBDA CBD CBN CBG U.S. Patent Jun . 2 , 2020 Sheet 4 of 4 US 10,669,248 B2 Fig . 5 Representative Terpene , Terpene Alcohol, and Terpenoid Concentrations in Concentrate Produced from Liquid Distillate 3.96 % Sl 2.33 % 1.2 % poods 0.6 % Humulene Guaiol(-) Linalool AlphaTerpineol- Myrcene Eucalyptol Limonene Nerolidol Alpha-Terpinene Borneol -Isopulegol Beta-Caryophyllene BisabololAlpha-() OxideCaryophyllene US 10,669,248 B2 1 2 METHODS TO CHEMICALLY MODIFY show a predicted, single - step , cyclic chemical reaction cata CANNABINOIDS lyzed by a first THCA molecule that results in the decar boxylation of a second THCA molecule . PRIORITY CLAIM FIG . 3 is a bar graph depicting the THCA , THC , CBDA , 5 CBD , CBN , and CBG concentrations found in a typical This patent application claims priority to U.S. Provisional sample of USDA organic industrial hemp. Patent Application No.62 /717,235 , filed Aug. 10 , 2018 , and FIG . 4 is a bar graph depicting the THCA , THC , CBDA , U.S. Provisional Patent Application No. 62/ 803,408 , filed CBD , CBN , and CBG concentrations found in four different Feb. 8 , 2019, each of which is incorporated by reference in concentrate products produced according to methods dis its entirety . 10 closed in this patent document. FIG . 5 is a bar graph depicting terpene , terpene alcohol , BACKGROUND and terpenoid concentrations found in two different concen trate products produced according to methods disclosed in Industrial hemp and other forms of cannabis contain a this patent document. variety of different cannabinoids , which predominantly each 15 contain a carboxyl group . These cannabinoid carboxylic DETAILED DESCRIPTION acids bind the human cannabinoid receptors with relatively low affinity . The production of therapeutic pharmaceuticals The present disclosure describes methods to rapidly and psychoactive drugs from cannabis therefore generally decarboxylate cannabinoids without generating appreciable utilizes a decarboxylation step, which typically involves 20 quantities of undesirable side products . Various methods prolonged heating . This heating also generally introduces comprise ( 1 ) rapidly vaporizing and decarboxylating a can other chemical modifications that are typically undesirable . nabinoid , and then ( 2 ) contacting the vaporized , decarboxy Marijuana produces tetrahydrocannabinolic acid lated cannabinoid with a heat sink to condense the decar (“ THCA " ) , for example , which lacks robust pharmacologi boxylated cannabinoid . cal effects . THCA is converted into the psychoactive mol- 25 Cannabinoids are typically decarboxylated by heating . ecule tetrahydrocannabinol ( “ THC ” ) by decarboxylation , Traditional hydrocarbon -based extraction methods typically which occurs when marijuana is smoked . THC is commer extract cannabinoid carboxylic acids from cannabis prior to cially produced from THCA by heating the THCA for decarboxylation . The extracted cannabinoid carboxylic several hours . Prolonged heating nevertheless results in acids are typically then converted into activated decarboxy undesirable side products . THCA can be oxidized , for 30 lated cannabinoids by heating in a vacuum oven for several example , into cannabinolic acid (“ CBNA ” ) , which decom hours. The inventors modelled possible reaction mecha poses into cannabinol (“ CBN ” ) . CBNA lacks well- known nisms for the decarboxylation and determined that cannabi pharmacological properties, and CBN causes drowsiness . noid carboxylic acids can self - catalyze the reaction . Industrial hemp similarly produces cannabidiolic acid According to the self -catalyzed reaction mechanism , (“ CBDA ” ) , which lacks robust pharmacological effects . 35 decarboxylation can proceed in a single - step, cyclic reaction CBDA is converted into the pharmaceutical cannabidiol depicted in FIG . 1 , which shows a first 2,4 -dihydroxy - 3 (“ CBD ” ) by decarboxylation . CBD is commercially pro [( 1R ,OR ) -6 - isopropenyl - 3 -methylcyclohex - 2- en - 1 - yl ) -6 duced from CBDA by heating the CBDA for several hours . pentylbenzoic acid (“ CBDA ” ) molecule ( FIG . 1 , top ) cata Prolonged heating nevertheless results in undesirable side lyzing the decarboxylation of a second CBDA molecule products including CBN . 40 ( FIG . 1 , bottom ). Immediately prior to the reaction , the first The industrial production of decarboxylated cannabinoids and second CBDA molecules form two intermolecular also degrades and vaporizes other molecules found in can hydrogen bonds denoted by two long dotted lines in FIG . 1 . nabis including terpenes , terpene alcohols , terpenoids, and The hydrogen bond depicted by the top -most dotted line is flavonoids, which often impart favorable characteristics to between an electron pair of the carbonyl oxygen of the first products containing cannabinoids including favorable flavor 45 CBDA molecule (FIG . 1 , “ a ” ) and the hydroxyl proton of the and aroma. second CBDA molecule (FIG . 1 , “ b ” ) . The hydrogen bond Improved methods to decarboxylate cannabinoids are depicted by the bottom -most dotted is between the pi desirable . electron cloud of the second CBDA molecule ( FIG . 1 , “ g ” ) and the carboxylic acid proton of the first CBDA molecule SUMMARY 50 (FIG . 1 , “ h ” ) . An intramolecular hydrogen bond also forms between an electron pair of the hydroxyl oxygen of the Various aspects of this patent document relate to the rapid , second CBDA molecule (FIG . 1 , “ c ” ) and the carboxylic stoichiometric decarboxylation of cannabinoid carboxylic acid proton of the second CBDA molecule (FIG . 1 , " d " ) . acids ( for example , CBDA or THCA ) in the gas phase The predicted , single - step , cyclic reaction shown in FIG . followed by the condensation of a decarboxylated cannabi- 55 1 proceeds by converting the three hydrogen bonds into noid product ( for example , CBD or THC ) . covalent bonds , breaking four single bonds , converting two single bonds into double bonds, and converting a double BRIEF DESCRIPTION OF THE DRAWINGS bond into a single bond . The hydrogen bond between an electron pair of the carbonyl oxygen of the first CBDA FIG . 1 depicts the skeletal formula of two CBDA mol- 60 molecule (FIG . 1 , “ a ” ) and the hydroxyl proton of the second ecules before a first CBDA molecule catalyzes the decar CBDA molecule (FIG . 1 , “ b ” ) becomes a covalent bond , boxylation of a second CBDA molecule to regenerate the which converts the double bond between the carbonyl first CBDA molecule and to produce CBD and carbon oxygen (FIG .
Load more

Recommended publications
  • Uncovering the Psychoactivity of a Cannabinoid from Liverworts Associated with a Cyano Cannabinoids
    SCIENCE ADVANCES | RESEARCH ARTICLE NEUROPHYSIOLOGY Copyright © 2018 The Authors, some rights reserved; Uncovering the psychoactivity of a cannabinoid from exclusive licensee American Association liverworts associated with a legal high for the Advancement A. Chicca1, M. A. Schafroth2, I. Reynoso-Moreno1, R. Erni2, V. Petrucci1, of Science. No claim to 2 1 original U.S. Government E. M. Carreira *, J. Gertsch * Works. Distributed under a Creative Phytochemical studies on the liverwort Radula genus have previously identified the bibenzyl (−)-cis-perrottetinene Commons Attribution 9 9 (cis-PET), which structurally resembles (−)-D -trans-tetrahydrocannabinol (D -trans-THC) from Cannabis sativa NonCommercial L. Radula preparations are sold as cannabinoid-like legal high on the internet, even though pharmacological data License 4.0 (CC BY-NC). are lacking. Herein, we describe a versatile total synthesis of (−)-cis-PET and its (−)-trans diastereoisomer and demonstrate that both molecules readily penetrate the brain and induce hypothermia, catalepsy, hypolocomo- tion, and analgesia in a CB1 receptor–dependent manner in mice. The natural product (−)-cis-PET was profiled on major brain receptors, showing a selective cannabinoid pharmacology. This study also uncovers pharmacological 9 differences between D -THC and PET diastereoisomers. Most notably, (−)-cis-PET and (−)-trans-PET significantly 9 reduced basal brain prostaglandin levels associated with D -trans-THC side effects in a CB1 receptor–dependent manner, thus mimicking the action of the endocannabinoid 2-arachidonoyl glycerol. Therefore, the natural product (−)-cis-PET is a psychoactive cannabinoid from bryophytes, illustrating the existence of convergent evolution of bioactive cannabinoids in the plant kingdom. Our findings may have implications for bioprospecting and drug discovery and provide a molecular rationale for the reported effects upon consumption of certain Radula prepa- rations as moderately active legal highs.
    [Show full text]
  • Identification, Isolation and Functional Characterization of Prenyltransferases in Cannabis Sativa L
    Identification, isolation and functional characterization of prenyltransferases in Cannabis sativa L. Zur Erlangung des akademischen Grades eines Dr. rer. nat. von der Fakultät Bio- und Chemieingenieurwesen der Technischen Universität Dortmund Dissertation vorgelegt von M. Sc. Kathleen Pamplaniyil aus Viersen Dortmund 2016 2 Acknowledgments I would like to thank all people who supported me throughout the years of my Ph.D. thesis. First of all, I would like to express my gratitude towards Prof. Dr. Oliver Kayser (Chair of Technical Biochemistry, TU Dortmund) for his support and supervision throughout the time of my thesis. The discussions with him broadened my scientific knowledge and the work in his chair was instructive. Furthermore, I want to thank Dr. Felix Stehle for guidance and support during the last two years of my thesis. The interesting discussions about the course of my experiments were inspirational. In addition my sincere thanks are given to Prof. Dr. Jörn Kalinowski (Research group Microbial genomics and biotechnology, Center for Biotechnology) and Oliver Rupp (Chair Bioinformatics and Systems Biology, University Giessen) for their generous support during the in silico analysis. Moreover, I want to express my appreciation to Prof. Dr. Heribert Warzecha (Department of Biology, TU Darmstadt) and Jascha Volk (Department of Biology, TU Darmstadt) who supported me with their knowledge and equipment during the transient expression in tobacco plants. I am very thankful for the financial support of the Ministry of Innovation, Science and Research of the German Federal State of North Rhine Westphalia (NRW) and TU Dortmund. Special thanks go to my colleagues especially Verena, Schütz, Evamaria Gruchattka, Friederike Ullrich, Friederike Degenhardt, Bastian Zirpel and Laura Kohnen for their contribution in scientific discussions and the good time we shared together besides the work in the lab.
    [Show full text]
  • Phytocannabinoids Origins and Biosynthesis Gülck, Thies; Møller, Birger Lindberg
    Phytocannabinoids Origins and Biosynthesis Gülck, Thies; Møller, Birger Lindberg Published in: Trends in Plant Science DOI: 10.1016/j.tplants.2020.05.005 Publication date: 2020 Document version Publisher's PDF, also known as Version of record Document license: CC BY-NC-ND Citation for published version (APA): Gülck, T., & Møller, B. L. (2020). Phytocannabinoids: Origins and Biosynthesis. Trends in Plant Science, 25(10), 985-1004. https://doi.org/10.1016/j.tplants.2020.05.005 Download date: 03. Dec. 2020 Trends in Plant Science Feature Review Phytocannabinoids: Origins and Biosynthesis Thies Gülck1,2,3,* and Birger Lindberg Møller1,2,3,* Phytocannabinoids are bioactive natural products found in some flowering Highlights plants, liverworts, and fungi that can be beneficial for the treatment of human Phytocannabinoids are bioactive terpe- ailments such as pain, anxiety, and cachexia. Targeted biosynthesis of cannabi- noids that were thought to be exclusive noids with desirable properties requires identification of the underlying genes to Cannabis sativa, but have now also been discovered in Rhododendron spe- and their expression in a suitable heterologous host. We provide an overview cies, some legumes, the liverwort genus of the structural classification of phytocannabinoids based on their decorated Radula,andsomefungi. resorcinol core and the bioactivities of naturally occurring cannabinoids, and we review current knowledge of phytocannabinoid biosynthesis in Cannabis, Many cannabinoids display promising non-hallucinogenic bioactivities that are Rhododendron,andRadula species. We also highlight the potential in planta determined by the variable nature of the roles of phytocannabinoids and the opportunity for synthetic biology approaches side chain and prenyl group defined by based on combinatorial biochemistry and protein engineering to produce canna- the enzymes involved in their synthesis.
    [Show full text]
  • Beyond Cannabis: Plants and the Endocannabinoid System
    TIPS 1329 No. of Pages 12 Review Beyond Cannabis: Plants and the Endocannabinoid System Ethan B. Russo1,* Plants have been the predominant source of medicines throughout the vast Trends majority of human history, and remain so today outside of industrialized socie- The endocannabinoid system (ECS) is ties. One of the most versatile in terms of its phytochemistry is cannabis, whose a homeostatic regulator of neurotrans- investigation has led directly to the discovery of a unique and widespread mitter activity and almost every other homeostatic physiological regulator, the endocannabinoid system. While it physiological system in the body. had been the conventional wisdom until recently that only cannabis harbored Its name derives from cannabis, the active agents affecting the endocannabinoid system, in recent decades the plant that produces cannabinoids (tet- fi rahydrocannabinol, cannabidiol, caryo- search has widened and identi ed numerous additional plants whose compo- phyllene, and others), and whose nents stimulate, antagonize, or modulate different aspects of this system. These investigation elucidated the myriad include common foodstuffs, herbs, spices, and more exotic ingredients: kava, functions of the ECS. chocolate, black pepper, and many others that are examined in this review. In the past two decades, additional research has discovered that many Overview of the Endocannabinoid System other plant foods and herbs modulate Cannabis (Cannabis sativa) has been an important tool in the herbalist's arsenal and the medical the ECS directly and indirectly. Advan- pharmacopoeia for millennia, but it has only been in the past 25 years that science has provided cing this knowledge may have impor- tant implications for human health and a better understanding of its myriad benefits.
    [Show full text]
  • Entheogens, the Conscious Brain and Existential Reality Chris King Complementary Video: Entheogens, Culture and the Conscious Brain
    Entheogens, the Conscious Brain and Existential Reality Chris King Complementary video: Entheogens, Culture and the Conscious Brain http://youtu.be/pY2MDqdv-No Abstract: The purpose of this article is to provide a ‘state of the art’ research overview of what is currently known about how entheogens, including the classic psychedelics, affect the brain and transform conscious experience through their altered receptor dynamics, and to explore their implications for understanding the conscious brain and its relationship to existential reality, and their potential utility in our cultural maturation and understanding of the place of sentient life in the universe. Contents 1. Cultural and Historical Introduction 2. The Enigma of Subjective Consciousness 3. Fathoming the Mind-Brain Relationship and Experiential Modalities 4. Doors of Perception: Classic Psychedelics and Serotonin Receptor Agonists 5. Doors of Dissociation: Ketamine and the NMDA Receptor Antagonists 6. Salvinorin-A and κ-Opioid Dissociatives 7. Cannabinoids 8. Entactogens 9. Doors of Delirium: Scopolamine and Muscarinic Acetyl-choline Antagonists 10. Safety Considerations of Psychedelic Use and Global Drug Policy 11. An Across-the-Spectrum Case Study 12. Why the Neurotransmitters: Cosmology and Evolution 13. Conclusion 14. References 1: Cultural and Historical Introduction Human societies have been actively using psychoactive substances since the earliest cultures emerged. In “The Alchemy of Culture” Richard Rudgley notes that European cave depictions, from the paleolithic on, abound with both herbivorous animals of the hunt and geometrical entopic patterns similar to the phosphenes seen under sensory withdrawal and under the effects of psychotropic herbs. By the time we find highly-decorated pottery ‘vase supports’ in Middle Neolithic France, we have evidence consistent with their ritual use as opium braziers.
    [Show full text]
  • Isolation, Identification and Characterization of Endophytes From
    Isolation, identification and characterization of endophytes from Cannabis sativa L. and Radula marginata Zur Erlangung des akademischen Grades eines Dr. rer. nat. von der Fakultät Bio- und Chemieingenieurwesen der Technischen Universität Dortmund genehmigte Dissertation vorgelegt von M.Sc. Parijat Kusari aus Kolkata, Indien Tag der mündlichen Prüfung: 15.12.2014 1. Gutachter: Prof. Dr. Oliver Kayser 2. Gutachter: Prof. Dr. Peter Proksch Dortmund 2014 “Learn from yesterday, live for today, hope for tomorrow. The important thing is not to stop questioning” -Albert Einstein Dedicated to my parents I Acknowledgements ACKNOWLEDGEMENTS I would like to take this opportunity to express my sincere appreciation and gratitude to all the people who accompanied and supported me in accomplishing my thesis. I express my deepest gratitude to my supervisor Prof. Dr. Oliver Kayser (Department of Biochemical and Chemical Engineering, Chair of Technical Biochemistry, TU Dortmund) for his credence and impeccable support towards my scientific endeavors. His scientific discussions, constant guidance and remarkable motivation propelled me to overcome the challenges and move ahead with new vision. There was always a lot to learn from his critical comments on manuscript and intensive ideas. I sincerely thank him for giving me the privilege to work under his exuberant supervision and guidance. I express my heartfelt thanks to Prof. Dr. Dr.h.c. Michael Spiteller (Institute of Environmental Research, INFU, Department of Chemistry and Chemical Biology, Chair of Environmental Chemistry and Analytical Chemistry, TU Dortmund) for his incessant scientific thoughts and guidance on various aspects of my research work. His critical suggestions and generous help has always inspired and encouraged me to enliven my scientific intentions.
    [Show full text]
  • Novel Chemical Probes for the Cannabinoid System
    Research Collection Doctoral Thesis Novel Chemical Probes for the Cannabinoid System Author(s): Westphal, Matthias V. Publication Date: 2017 Permanent Link: https://doi.org/10.3929/ethz-b-000255663 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 24543 Novel Chemical Probes for the Cannabinoid System A dissertation submitted to ETH ZURICH for the degree of DOCTOR OF SCIENCES presented by MATTHIAS V. WESTPHAL M.Sc. LMU Munich born on 16.07.1987 Citizen of the Federal Republic of Germany Accepted on the recommendation of Prof. Dr. Erick M. Carreira, examiner Prof. Dr. Pablo Rivera-Fuentes, co-examiner 2017 i Acknowledgements Throughout the last three decades I was very lucky to receive support by so many individuals to whom I am greatly indebted. First and foremost, I wish to thank my family and friends – you are awesome. Many thanks to my mom Regine and dad Rolf, to Günter, Tante Inge, Omama and Opapa for your everlasting support, for believing in me and for the financial safety to focus on my goals. Thank you Veronika and Arabella for being great siblings. And of course thanks to my longtime friends in the Weinheim area. I consider myself very fortunate that we have been keeping in touch throughout the last decade. During my early education I have had a number of outstanding teachers. I would like to thank Ms. B. Raepple and Ms. R. Pichl for their unique ways of teaching as well as Mr.
    [Show full text]
  • Natural Product Reports
    Volume 33 Number 12 December 2016 Pages 1347–1448 Natural Product Reports www.rsc.org/npr ISSN 0265-0568 REVIEW ARTICLE Lumír Ondřej Hanuš, Giovanni Appendino et al. Phytocannabinoids: a unifi ed critical inventory Natural Product Reports REVIEW View Article Online View Journal | View Issue Phytocannabinoids: a unified critical inventory ı *a b c Nat. Prod. Rep. Lum´r Ondˇrej Hanuˇs, Stefan Martin Meyer, Eduardo Munoz,˜ Orazio Taglialatela- Cite this: ,2016,33, d e 1357 Scafati and Giovanni Appendino* Covering up to January 2016 Cannabis sativa L. is a prolific, but not exclusive, producer of a diverse group of isoprenylated resorcinyl polyketides collectively known as phytocannabinoids. The modular nature of the pathways that merge into the phytocannabinoid chemotype translates in differences in the nature of the resorcinyl side-chain and the degree of oligomerization of the isoprenyl residue, making the definition of phytocannabinoid elusive from a structural standpoint. A biogenetic definition is therefore proposed, splitting the phytocannabinoid chemotype into an alkyl- and a b-aralklyl version, and discussing the relationships between phytocannabinoids from different sources (higher plants, liverworts, fungi). The startling Creative Commons Attribution 3.0 Unported Licence. diversity of cannabis phytocannabinoids might be, at least in part, the result of non-enzymatic transformations induced by heat, light, and atmospheric oxygen on a limited set of major constituents (CBG, CBD, D9-THC and CBC and their corresponding acidic versions), whose degradation is detailed to emphasize this possibility. The diversity of metabotropic (cannabinoid receptors), ionotropic (thermos- TRPs), and transcription factors (PPARs) targeted by phytocannabinoids is discussed. The integrated Received 13th June 2016 inventory of these compounds and their biological macromolecular end-points highlights the DOI: 10.1039/c6np00074f opportunities that phytocannabinoids offer to access desirable drug-like space beyond the one www.rsc.org/npr associated to the narcotic target CB1.
    [Show full text]
  • Dortmund 2018
    Evaluation of C-prenylating enzymes for the heterologous biosynthesis of cannabigerolic acid Zur Erlangung des akademischen Grades eines Dr. rer. nat. von der Fakultät Bio- und Chemieingenieurwesen der Technischen Universität Dortmund genehmigte Dissertation vorgelegt von M.Sc. Sara Friederike Degenhardt aus Mainz Tag der mündlichen Prüfung: 09.10.2018 1. Gutachter: Prof. Dr. Dr. h.c. Oliver Kayser 2. Gutachter: Prof. Dr. Heribert Warzecha Dortmund 2018 i Acknowledgements Acknowledgements I would like to express my appreciation and gratitude to all the people who supported, encouraged and motivated me over the last years. Firstly, I would like to express my gratitude to my supervisor Prof. Dr. Dr. h.c. Oliver Kayser (Chair of Technical Biochemistry, TU Dortmund, Germany) for his support and guidance over the last years. He kept me going when times were though and offered me the opportunity of a Short-Term Scientific Mission in the group of Prof. Poul Nissen (Aarhus University, Denmark). Thanks to Dr. Felix Stehle (Chair of Technical Biochemistry, TU Dortmund, Germany) for helpful suggestions as well as his constant support and advice. I am also thankful for the prediction of NphB mutants. I thank PD Dr. Wolfgang Brandt (Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Halle (Saale), Germany) for generating the structural model of NphB complexed with GSPP and OA. Furthermore, I would like to thank the Ministry of Innovation, Science and Research of the German Federal State of North Rhine-Westphalia and TU Dortmund for awarding me with a scholarship from the CLIB-Graduate Cluster Industrial Biotechnology (CLIB2021). I am thankful to the European Cooperation in Science and Technology (COST) for financing my Short-Term Scientific Mission (STSM) in the Nissen group at the University of Aarhus (Denmark) (PlantEngine, COST Action FA1006).
    [Show full text]
  • Cannabis Sativa: a Comprehensive Ethnopharmacological Review of a Medicinal Plant with a Long History T
    Journal of Ethnopharmacology 227 (2018) 300–315 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jethpharm Review Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history T Sara Anna Boninia, Marika Premolia, Simone Tambarob, Amit Kumarc, Giuseppina Maccarinellia, ⁎ Maurizio Memoa, Andrea Mastinua, a Department of Molecular and Translational Medicine, Division of Pharmacology, University of Brescia, Brescia, Italy b Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden c Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Huddinge, Sweden ARTICLE INFO ABSTRACT Keywords: Ethnopharmacological relevance: Cannabis sativa L. (C. sativa) is an annual dioecious plant, which shares its Cannabis sativa L. origins with the inception of the first agricultural human societies in Asia. Over the course of time different parts Ethnobotany of the plant have been utilized for therapeutic and recreational purposes, for instance, extraction of healing oils Phytocannabinoids from seed, or the use of inflorescences for their psychoactive effects. The key psychoactive constituent in C. sativa Terpenoids is called Δ-9-tetrahydrocannabinol (D9-THC). The endocannabinoid system seems to be phylogenetically an- Endocannabinoids cient, as it was present in the most primitive vertebrates with a neuronal network. N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG) are the main endocannabinoids ligands present in the animal kingdom, and the main endocannabinoid receptors are cannabinoid type-1 (CB1) receptor and cannabinoid type- 2 (CB2) receptor. Aim of the study: The review aims to provide a critical and comprehensive evaluation, from the ancient times to our days, of the ethnological, botanical, chemical and pharmacological aspects of C.
    [Show full text]
  • Natural Products from Bryophytes: from Basic Biology to Biotechnological Applications
    Downloaded from orbit.dtu.dk on: Oct 04, 2021 Natural Products from Bryophytes: From Basic Biology to Biotechnological Applications Horn, Armin; Pascal, Arnaud; Lonarevi, Isidora; Volpatto Marques, Raíssa; Lu, Yi; Miguel, Sissi; Bourgaud, Frederic; Thorsteinsdóttir, Margrét; Cronberg, Nils; Becker, Jörg D. Total number of authors: 12 Published in: Critical Reviews in Plant Sciences Link to article, DOI: 10.1080/07352689.2021.1911034 Publication date: 2021 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Horn, A., Pascal, A., Lonarevi, I., Volpatto Marques, R., Lu, Y., Miguel, S., Bourgaud, F., Thorsteinsdóttir, M., Cronberg, N., Becker, J. D., Reski, R., & Simonsen, H. T. (2021). Natural Products from Bryophytes: From Basic Biology to Biotechnological Applications. Critical Reviews in Plant Sciences, 40(3), 191-217. https://doi.org/10.1080/07352689.2021.1911034 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
    [Show full text]
  • Terza Edizione
    Dipartimento del Farmaco Istituto Superiore di Sanità - Roma SmartDrugs Terza edizione Il progetto è stato realizzato con il supporto tecnico e logistico del Comando Carabinieri per la tutela della salute (NAS) nelle fasi di pianificazione delle verifiche e di individuazione degli Smart Shop, dei siti internet e nel reperimento delle sostanze da analizzare. Reparto Farmacodipendenza, Tossicodipendenza e Doping Osservatorio Fumo Alcol e Droga Dipartimento del Farmaco Istituto Superiore di Sanità Viale Regina Elena, 299 - 00161 Roma Tel. 06 49902909 Fax 06 49902016 E-mail: [email protected] Volume realizzato grazie al finanziamento concesso dalla Presidenza del Consiglio dei Ministri Dipartimento della Gioventù e del Servizio Civile Nazionale a valere sul “Fondo per le Politiche giovanili” SmartDrugs Terza edizione Simona Pichini e Roberta Pacifici con Emilia Marchei, Ilaria Palmi, Manuela Pellegrini, Maria Concetta Rotolo Dipartimento del Farmaco - Osservatorio Fumo Alcol e Droga Istituto Superiore di Sanità - Roma Gen. D. Cosimo Piccinno, Magg. Pietro Della Porta, Cap. Francesco Saggio, Cap. Dario Praturlon Comando Carabinieri per la tutela della salute (NAS) Ufficio Comando - Sezione Operazioni Reparto Analisi Gruppo di lavoro dell’Osservatorio Fumo Alcol e Droga Antonella Bacosi, Simonetta Di Carlo, Rita di Giovannandrea, Patrizia Gori, Silvia Graziano, Laura Martucci, Luisa Mastrobattista, Adele Minutillo, Claudia Mortali, Giulia Scaravelli, Renata Solimini, Roberta Spoletini, Giacomo Toth Si ringraziano Rosanna Cammarano, Alessandra Ceccarini, Italo Gentilini, Scilla Pizzarelli del “Settore Documentazione” dell'Istituto Superiore di Sanità Indice Prefazione pag. 000 Presentazione pag. 000 Introduzione pag. 000 1 “Smart Drugs” di origine vegetale 1.1 Acorus calamus pag. 000 1.2 Amanita muscaria pag. 000 1.3 Anadenanthera peregrina pag.
    [Show full text]