University of Groningen The medicinal chemistry of aryl triflates Barf, Tjeerd Andries IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1996 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Barf, T. A. (1996). The medicinal chemistry of aryl triflates: as applied to 5-HT1A and 5-HT1D receptor ligands. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy 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. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 23-09-2021 The Medicinal Chemistry of Aryl Triflates as applied to 5-HT 1A and 5-HT 1D Receptor Ligands RIJKSUNIVERSITEIT GRONINGEN The Medicinal Chemistry of Aryl Triflates as applied to 5-HT 1A and 5-HT 1D Receptor Ligands PROEFSCHRIFT ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. van der Woude, in het openbaar te verdedigen op vrijdag 4 oktober 1996 des namiddags te 2.45 uur door Tjeerd Andries Barf geboren op 18 april 1967 te Groningen Promotor Prof. Dr. H. V. Wikström Co-promotor Dr. C. J. Grol Life is like a box of chocolate.... You never know what you gonna get Forrest Gump Voor mijn ouders, Arend & Wimmy Promotiecommissie Prof. Dr. D. Nichols Prof. Dr. B. Olivier Prof. Dr. B.L. Feringa Paranimfen Lynet Rooks Arwin Ridder ISBN 90 367 0681 5 NUGI 746 Cover design : Tjeerd Barf / “The only antimigraine agent that gives you the headache.” The 3-D stereogram was generated with Crosseye, available on Internet Printing : PrintPartners Ipskamp bv An electronic version of this thesis in Adobe PDF-format is available on the Internet: WWW : http://docserver.ub.rug.nl/eldoc/dis/science/t.a.barf Gopher : gopher://docserver.ub.rug.nl/11/eldoc/dis/science/t.a.barf Chapter 1.....................................................................................1 Introduction 1.1 History.................................................................................................................... 1 1.2 Serotonin Receptors............................................................................................. 1 Classification............................................................................................. 1 Evolutionary Perspectives....................................................................... 3 1.3 5-HT1A Receptors................................................................................................... 4 Distribution and Function ....................................................................... 4 Structural Aspects..................................................................................... 5 Pharmacophore of the 5-HT1A Receptor................................................ 6 1.4 5-HT1A Receptor Agonists and Antagonists (SAR).......................................... 7 Indolealkylamines .................................................................................... 7 Aminotetralins and Analogues ............................................................... 8 Arylpiperazines and Analogues ............................................................11 Aryloxyalkylamines................................................................................12 1.5 5-HT1D Receptors..................................................................................................13 Distribution and Function ......................................................................13 Structural Aspects....................................................................................15 The 5-HT1D Receptor Pharmacophore..................................................16 1.6 5-HT1A Receptor Agonists and Antagonists (SAR).........................................16 1.7 Objective and Outline..........................................................................................20 1.8 References.............................................................................................................23 Chapter 2....................................................................................27 Synthesis and Pharmacological Evaluation of 2-Aminotetralin Derivatives 2.1 Introduction...........................................................................................................27 2.2 Chemistry...............................................................................................................29 Preparation and Resolution of (±)-8-OSO2CF3-PAT..........................29 Preparation and Resolution of Cis-(±)-8-OSO2CF3-MPAT...............31 Preparation of Cis- and Trans-8-OSO2CF3-MMAT............................32 Cis- and Trans-assignment.....................................................................34 2.3 Pharmacology.......................................................................................................35 Receptor Binding.....................................................................................35 In Vivo Biochemistry of (R)- and (S)-8-OSO2CF3-PAT .....................35 Locomotor Activity and Gross Behavioural Observations ...............37 Oral Bioavailability and In Vitro Metabolism of (R)-8-OSO2CF3-PAT ....................................................................................................................38 Hypothermia.............................................................................................38 2.4 Results and Discussion........................................................................................39 Structure-Affinity Relationships...........................................................39 Structure-Activity Relationships...........................................................39 2.5 Experimental Section...........................................................................................42 2.6 References.............................................................................................................52 Chapter 3....................................................................................53 Potential Anxiolytic Properties of ( R)-8-SO 2CF 3-PAT 3.1 Introduction...........................................................................................................53 3.2 Results....................................................................................................................54 Conditioned Defensive Burying............................................................54 Conditioned Fear of Footshock.............................................................55 Elevated Plus-maze .................................................................................55 Effect on the 5-HIAA/5-HT ratio in Various Rat Brain Regions......56 3.3 Discussion .............................................................................................................56 3.4 Conclusion.............................................................................................................59 3.5 Experimental Section...........................................................................................60 3.6 References.............................................................................................................63 Chapter 4....................................................................................65 5-HT 1D Receptor Agonist Properties of Novel 5- [[(Trifluoromethyl)sulfonyl]oxy]indolylethylamines 4.1 Introduction...........................................................................................................65 4.2 Chemistry...............................................................................................................67 4.3 Pharmacology.......................................................................................................69 Receptor Binding.....................................................................................69 cAMP Assay .............................................................................................69 In Vivo Biochemistry...............................................................................69 Hypothermia.............................................................................................71 4.4 Results and Discussion........................................................................................71 Structure-Affinity and Structure-Activity Relationships..................71 Pharmacology...........................................................................................72 4.5 Experimental Section...........................................................................................74 4.6 References.............................................................................................................83 Chapter 5....................................................................................85 5-(Sulfonyl)oxy-tryptamines and