Complete Dissertation

VU Research Portal Histamine H-receptor agonists and antagonists ter Laak, A.M. 1995 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) ter Laak, A. M. (1995). Histamine H-receptor agonists and antagonists: molecular modeling and drug design. 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 ? 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. E-mail address: [email protected] Download date: 06. Oct. 2021 Histamine H1~receptor Agonists and Antagonists Molecular Modeling and Drug Design , Ton tel' Laak Histamine HI-receptor Agonists and Antagonists Molecular Modeling and Drug Design VRIJE UNIVERSlTEIT Histamine HI-receptor Agonists and Antagonists Molecular Modeling and Drug Design ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Vrije Universiteit te Amsterdam, op gezag van de rector magnificus prof.dr E. Boeker, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der scheikunde op maandag 16 oktober 1995 te 13.45 uur in het hoofdgebouw van de universiteit, De Boelelaan 1105 door Antonius Marinus ter Laak geboren te Delft Promotor prof.dr H. Timmerman Copromotor dr G.M. Donne-Op den Kelder Referent prof.dr H. Wikstrom The inve'stigations described in this thesis were supported by a grant of the Netherlands Technology Foundation (STW/NWO) and perfonned at the Department ofPhannacochernistry, Vrije Universiteit, Amsterdam, The Netherlands. Part of the thesis work (Chapter 4) was perfonned at the Institut de Chimie Therapeutique, Ecole de Phannacie, BEP, Lausanne, Switzerland. Part of the studies presented in Chapter 5 were perfonned at the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands. © A.M. ter Laale, Amsterdam 1995 No part of this book may be reproduced in any form or by any means without permission from the author. Cover design: SETOR V.4.13.4, University of British Colombia (1995). CONTENTS Page CHAPTER 1 Introduction 1 SECTION I Studies towards the rational design of non-sedating histamine HI-antagonists CHAPTER 2 Rational design of non-sedating histamine HI-antagonists; a short introduction to section I 9 CHAPTER 3 Is there a difference in affinity of histamine HI-receptor antagonists for CNS- and peripheral receptors? An in vitro study 13 CHAPTER 4 Lipophilicity and hydrogen bonding capacity ofH l-antihistaminic agents in relation to their central sedative side-effects 23 CHAPTERS Influence ofprotein binding on the central sedative side-effects of histamine HI-receptor antagonists 39 SECTION II Molecular modeling of histamine HI-receptor agonist and antagonist binding sites CHAPTER 6 QSAR and molecular modeling studies on histamine HI-receptor antagonists; an introductory review 59 CHAPTER 7 The histamine HI-receptor antagonist binding site. A stereoselective pharmacophoric model based upon (semi-)rigid HI-antagonists and including a known interaction site on the receptor 89 CHAPTER 8 Modeling of the histamine H I-receptor using bacteriorhodopsin as a template; a critical evalution 111 CHAPTER 9 Modeling and mutation studies on the histamine HI-receptor agonist binding site revealing different binding modes for H l-agonists; Asp116 (TMlII) has a constitutive role in receptor stimulation 129 SECTION III Summary and Conclusions CHAPTER 10 Summary and Conclusions 151 References 157 List ofAbbreviations 169 List ofPublications 171 Dankwoord 173 Introduction ------------ CHAPTER 1------------ INTRODUCTION Introduction At the beginning of this century, not long after the first synthesis of 2-(imidazol-4 yl)ethylamine (Windaus and Vogt, 1907), this compound (histamine) was found to be vasoactive and a potent stimulator of smooth muscle contraction (Dale and Laidlow, 1910 1911). From then on, it became apparent that histamine has many more pharmacological actions and is released upon injurious stimulation of many human and animal tissues. Therefore, in early years, histamine was particularly seen as an important mediator in certain pathological conditions (Le., injuries, allergic reactions). Bovet and Staub (1937) were the first investigators to synthesize (weak) competitive inhibitors of the histamine response (i.e. piperoxan and thymoxyethyldiethylamine). The discovery of the first relatively potent HI-antagonist with two aromatic rings (antergan, Halpern et al., 1942) was the initiation of an enormous step forward in the field of histamine research: within ten years, chemists around the world synthesized more than 5000 antihistaminic compounds (Bovet, 1959). Today many of these early compounds, which are now known as 'classical' histamine HI-antagonists, are still used as therapeutic drugs (Le., diphenhydramine, promethazine, chlorphenyramine, mepyramine and tripelenamine) in allergy and occasionally sleep disturbances. Histamine receptor subtypes It was recognized by Ash and Schild (1966) that some pharmacological actions of histamine (stimulation <;,f gastric acid secretion and uterus contraction) were not antagonized by drugs such as diphenhydramine and mepyramine and that in various organs there were differences in the structure-activity relationships of histamine agonists. These findings led the authors to suggest the existence of a second subtype ofhistamine receptor. Soon thereafter, the histamine H2-receptor was defined by Black et al. (1972), who synthesized and reported the first potent histamine antagonist ofgastric acid secretion (the H2-antagonist burimamide). About ten years later, a third histamine receptor (H3) was discovered by the group of -I- Chapter 1 Schwartz (Arrang et al., 1983). This histamine H3-receptor, located on nerve endings in the central nervous system (CNS) and characterized as a histamine autoreceptor, appears to playa regulatory role in neurotransmission both in central and peripheral neuronal systems. Since the discovery of, respectively, the H2- and H3-receptor, many selective and potent ligands have been synthesized for these receptors and tested for potential use as pharmacological tools and/or as drugs. These histamine H2- and H3-ligands are, in general, structurally quite different from those binding at HI-receptors (for detailed reviews: Casy et al., 1978; Cooper et aI., 1990; Leurs et aI., 1995). Therapeutic use ofhistamine HI-antagonists 'Antihistamines' or 'antihistaminics' are still commonly used terms for antagonists of the histamine HI-receptor, since they were the first histamine antagonists discovered. It was shown by Riley and West in 1953 that substantial amounts of histamine are stored in, and can be released by mast cells, present in various body tissues. Exposure to antigen, which binds . and activates IgE-type antibodies on mast cells, may cause a massive release of histamine by these cells (Le., in the lungs, skin or eyes). Histamine release may then be involved in various effects of an allergic reaction, Le. bronchoconstriction, vasodilation, progress of the allergic reaction (increased vasopermeability, stimulation of prostaglandin production) and even, in case of high systemic histamine concentrations, anaphylactic shock. Since the unwanted pharmacological action of histamine is often associated with degranulation of mast cells, the therapeutic use of antihistamines is, in theory, indicated for pathological conditions which display type I hypersensitivity reactions (urticaria, allergic rhinitis, conjunctivitis, hay fever, asthma and anaphylactic shock). Indeed, upon their introduction in the 1940s, inhaled or parental antihistamines appeared to offer protection against certain allergic reactions, Le. against bronchoconstriction caused by inhaled allergen or exercise challenge. Histamine HI-antagonists appeared, however, relatively ineffective upon oral administration, especially in the treatment of asthma (Rafferty and Holgate, 1988). In contrast to what was expected, the success of antihistamines as anti-allergic drugs with a broad application was not established. Two reasons can be given for the relatively poor success of classical antihistamines: firstly, many allergic mediators other than histamine, Le. eicasonoids (prostaglandins, thromboxanes, leukotrienes) and platelet activating factor (PAF), playa role in allergic reactions and may in some cases surpass the role of histamine. Secondly, classical antihistamines are known for displaying CNS and other side effects (sedation, dizziness, sleepiness, dry mouth, accomodation and gastrointestinal problems). These side effects, especially sedation, do not -2- Jntroduction allow the use of substantial high dosages needed for the treatment of asthma and have always been a serious drawback for the therapeutic use of classical histamine HI-antagonists. As a consequence, the clinical use of classical compounds is limited

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