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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. R. Thieme for dragging me into science. I wish to express my sincere gratitude to Prof. Erick M. Carreira for giving me the opportunity to pursue PhD studies under his supervision. I very much appreciate his trust in my abilities and the scientific freedom I was allowed to enjoy along with the chance to interact with various external collaborators in the exciting field of cannabinoid research. I am grateful to Prof. Pablo Rivera-Fuentes for taking over the co-examination of this thesis. Philipp Sondermann, Moritz Hönig, Adrian Bailey, Volker Berg, Dr. James Frank and Dr. David Petrone are most gratefully acknowledged for proof-reading the manuscript. The work described in this thesis would not have been possible without the help of many individuals outside of ETH. I am deeply indebted to Dr. Uwe Grether for his constant support of the chemical probes project. Elisabeth Zirwes and Dr. Christoph Ullmer are most gratefully acknowledged for biological testing of so many compounds in various assays. Further thanks go to Dr. Wolfgang Guba for homology modelling and to Dr. Mark Rogers-Evans for his support during the early days of the project. Special thanks go to Dr. James Frank, Prof. Dirk Trauner, Prof. Ken Mackie, Prof. Vsevolod Katritch and their coworkers for the exciting collaboration on photoswitchable THC-derivatives. I am grateful to Marjolein Soethoudt and Prof. Mario van der Stelt for evaluating multiple photoactivatable probes. Likewise, Dr. Andrea Martella and Prof. Laura Heitman are gratefully acknowledged for studying receptor binding kinetics. Prof. Dmitry Veprintsev and Tamara Miljus are thanked for pharmacological studies of various tool compounds. A huge thank you goes to Dr. Michael Schafroth and Roman Sarott ii for a great team effort. Roman, I wish you lots of success in further developing and expanding the project. Team cannabinoids! I want to thank all members of the Carreira lab. You have made this place and the time spent here truly special by any definition. It has been a pleasure and an honor to work with and to learn from you during the past years. In particular, I want to thank my early and late labmates Dr. Stefan Diethelm, Dr. Lorenz Schneider, Emma Robertson, Dr. Patrick Brady (aka Dr. Postdoc), Dr. Mathias fancy-pants Jacobsen, honorary H336-members Nicole Hauser and innovation manager Dr. Hannes Zipfel, Philipp Sondermann, Niels Sievertsen and Moritz Hönig. Thanks for countless coopen-sie sessions, for sharing one musical highlight after the other, and for your support during the ups and downs of our common journey. Further, I want to thank Marco Brandstätter, Dr. Christian Ebner, Dr. Simon Krautwald, Dr. Nikolas Huwyler, Dr. Simon Breitler and Prof. David Sarlah for various semi-scientific activities in- and outside the lab. Thanks to everyone for fun times in general and the very important lunchen-sie sessions in particular – to the G-floor people: anything can happen on Fridays. Thank you Anke Kleint for administrative help and fun chats, and thanks to my students Michael Imhof, Daniel Joss, Sebastian Hecko, Yuki Fuyuki and Franziska Elterlein for your contributions to the project. ETH Zurich offers a unique infrastructure for research. I would like to thank everyone involved in keeping this place running, in particular the friendly and extremely helpful colleagues of the NMR service, the great teams running the HCI-Shop, waste disposal and glassware cleaning as well as the mass spectrometry service. I wish all present and future members of the Carreira lab lots of success in your research and the best of luck in your personal activities also known as real life. iii Table of Contents Acknowledgements ..................................................................................................................... i Abstract ...................................................................................................................................... v Zusammenfassung .................................................................................................................... vii I. Introduction ........................................................................................................................ 1 1 Interrogation of Biological Systems with Chemical Probes ............................................... 1 1.1 Fluorescent Probes ....................................................................................................... 3 1.2 Covalent Binders ......................................................................................................... 4 2 Photopharmacology ............................................................................................................ 5 3 The Endocannabinoid System ............................................................................................. 8 4 Aim of this Work .............................................................................................................. 10 II. Novel Chemical Probes for the Cannabinoid Receptor 2 ................................................ 11 5 Background ....................................................................................................................... 13 6 Triazolopyrimidine-Derived Ligands ............................................................................... 15 6.1 Electrophilic Probes ................................................................................................... 20 6.1.1 Synthesis of N-unsubstituted Triazolopyrimidines ............................................ 21 6.1.2 Synthesis of Fluorosulfonyl Derivatives ............................................................ 22 6.2 Results and Discussion .............................................................................................. 26 6.2.1 In Vitro Pharmacology ....................................................................................... 26 6.2.2 Affinity Based Protein Tagging ......................................................................... 29 6.2.3 Preliminary Assessment of Receptor Kinetics ................................................... 31 6.3 Photoactivatable Probes ............................................................................................. 36 6.3.1 Synthesis of Diazirine Derivatives ..................................................................... 37 6.4 Results and Discussion .............................................................................................. 41 6.4.1 In Vitro Pharmacology ....................................................................................... 41 6.4.2 Photoaffinity Labeling ........................................................................................ 44 7 Conclusion and Outlook ................................................................................................... 47 8 Novel CB2 Selective Cannabinoids .................................................................................. 49 8.1 Background ................................................................................................................ 49 iv 8.2 Towards a CB2 Selective Covalent Binder ............................................................... 51 8.2.1 Synthesis and Evaluation of a Hybrid Cannabinoid ........................................... 53 8.3 Synthesis of Bifunctional Probes ............................................................................... 56 8.4 Alternative Access to Amine 128 and Cannabinoids of Increased Polarity .............. 60 8.4.1 Synthesis of Isomerically Pure Resorcinols ....................................................... 61 8.5 Synthesis of AM841 .................................................................................................. 66 8.6 Photoactivatable, CB2-Selective Cannabinoids ........................................................ 68 8.7 Results and Discussion .............................................................................................
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