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BENZODIAZEPINES and DERIVATIVES Overview, Analysis and Synthesis Bachelor’s degree final project University of Barcelona Faculty of Pharmacy BENZODIAZEPINES AND DERIVATIVES Overview, analysis and synthesis Elisabet Batlle Rocafort March 2018 Main scope: Pharmaceutical chemistry Secondary scopes: Pharmacology and therapeutics, Organic Chemistry This work is licensed under a Creative Commons license INDEX 1. ABSTRACT / RESUM ................................................................................ 1 2. INTEGRATION OF THE DIFFERENTS AREAS...................................................... 2 3. INTRODUCTION ..................................................................................... 3 3.1 Discovery and history .................................................................... 3 3.2 Benzodiazepines (BZDs) ................................................................. 4 3.3 Mechanism of action ..................................................................... 4 3.4 Specific BZD receptors .................................................................. 6 3.5 Chemical structure and structure-activity relationship (SAR) ..................... 6 3.6 Pharmacokinetics and pharmacodynamics ........................................... 7 3.7 Classification of BZDs .................................................................... 8 3.8 Abuse and dependence – problem presentation ..................................... 9 3.9 Adverse effects ........................................................................... 9 4. OBJECTIVES ....................................................................................... 11 5. MATERIALS AND METHODES .................................................................... 11 6. RESULTS AND DISCUSSION ...................................................................... 12 6.1 Synthesis of benzodiazepines......................................................... 12 6.2 Traditional uses and new discoveries ............................................... 15 6.3 A new discovery: BET inhibitors...................................................... 18 6.4 Analysis of the reasons that lead to abuse and addiction ........................ 20 6.5 “Z-drugs” or non-benzodiazepines .................................................. 22 6.6 Tolerance, dependence and withdrawal syndrome ............................... 24 7. CONCLUSIONS .................................................................................... 28 8. BIBLIOGRAPHY ................................................................................... 29 Benzodiazepines and derivatives; overview, analysis and synthesis ______________________________________________________________________________ 1. ABSTRACT / RESUM Benzodiazepines are widely used drugs for several indications. This study provides, on the one hand, a global vision of this family starting for their fortuitous discovery, the synthesis of their derivatives, their mechanism of action which is well known nowadays, the actual classification according to the chemical structure and the pharmacokinetic properties and their uses and indications, including the traditional and the new ones. On the other hand, the study is focused in the dependence and tolerance derived from their use, many times lead by a misuse of the patient, wrong prescriptions or extended treatments. A withdrawal program is proposed, including the important factors or criteria to success, with a slow and gradual reduction of these drugs to avoid relapse or severe adverse effects. New lines of research related to benzodiazepines are taken into account, including the new therapeutic uses but also the adverse effects in short and long-term. They are also analyzed the new discoveries concerning the non-benzodiazepinic drugs due to the close relation they have with benzodiazepines. ____________________________________________________________________________ Les benzodiazepines son medicaments àmpliament utilitzats per nombroses indicacions. Aquest treball proporciona, per una part, una visió global de la família començant pel seu descobriment fortuït, la síntesi dels seus derivats, el seu mecanisme d’acció àmpliament conegut a l’actualitat, la classificació actual segons estructura química i propietats farmacocinètiques i els seus pertinents usos i indicacions, tant els tradicionals com els mes nous. Per altre part, el estudi es centra en la dependència i tolerància derivada del ús d’aquests medicaments, molt cops per una mala utilització per part del pacient o per prescripcions errònies i/o massa extenses. També es proposa un model de programa de retirada que té en compte tots els factors necessaris per aconseguir reduir gradualment aquests medicaments, sense patir cap recaiguda ni efectes secundaris severs, fins a aconseguir-ho amb èxit. Es tenen en compte les línies de recerca actuals en relació a benzodiazepines, tant per nous usos terapèutics com per efectes secundaris, ja sigui a curt o llarg termini. També s’analitzen els nous descobriments pel que fa als derivats no benzodiazepínics ja que tenen una estreta relació amb les benzodiazepines. 1 Benzodiazepines and derivatives; overview, analysis and synthesis ______________________________________________________________________________ 2. INTEGRATION OF THE DIFFERENTS AREAS This study here presented is considered to be fundamentally multidisciplinary. The objective is not only to integrate the three specific areas but also to complement it with the knowledge acquired throughout all the career. These three areas are Pharmacology, toxicology and therapeutic chemistry, Organic chemistry and Pharmaceutical chemistry, being this last the principal. The main field of this project is Pharmaceutical chemistry, since one of the objectives is to understand the relations between the structure and the biological activity of these compounds. New discoveries in relation with these drugs are analyzed, with the objective of improve their properties and to find new clinical purposes. Organic chemistry has an important role too, concerning the synthesis of benzodiazepines and their chemical structure. The line of approach for the study is mainly between these two chemistries due to their close relation. Nevertheless, this project contains a wide part of characterization and description of the drug family, their mechanism of action and their biological activity, among others. All these sections can be classified within the framework of pharmacology, toxicology and therapeutic chemistry, as well as the clinical applications. To do a complete overview of a drug is necessary a global approach, but it is important to know how this three fields connect and participate within this study in particular. 2 Benzodiazepines and derivatives; overview, analysis and synthesis ______________________________________________________________________________ 3. INTRODUCTION 3.1 Discovery and history Many of the drugs that had represented a great advance in many therapeutic approaches were not the result of a rational design but of a consequence of casual observations, fortuitous discovers or serendipity. Way back then, a rational design didn’t guarantee the exit because the knowledge of the biological systems was not clear or complete. That happened in the beginning of the past century and many of the drugs used nowadays come from this type of discovery, from the curiosity of many investigators that decided to study the reason why they were not achieving their goals. Discovery starts with chemist Leo Sternbach and his research group, working in the Hoffman- La Roche laboratories in Nutley, New Jersey. They were trying to find new tranquilizers but, due to the limited knowledge of the processes occurring in the brain, they were taking an empirical approach: to search for a new class of drugs purely guided by modifications in the known chemical synthesis.1 In 1957, they serendipitously identified chlorodiazepoxide, the first benzodiazepine (BZD), while they were studying the activity of quinazoline oxide. They saw that the compound obtained was not a quinazoline-N3-oxide but a benzodiazepine-N4- oxide. With a posterior investigation, Sternbach himself managed to explain what happened.2 By 1960, Hoffmann-La Roche introduced the chlorodiazepoxide in clinical treatment under the brand name Librium® and it pursued molecular modifications to improve its activity. By the time of its introduction, it was felt that an explanation of the BZDs mechanism of action might be really helpful to understand the basis of anxiety. Diazepam (Valium®) followed in 1963, which was considered for a long time as the Head of the family. Initially, BZDs appeared to be less toxic and less prone to cause dependence than older drugs used for the same purposes as barbiturates. An important improvement compared to barbiturates was their lack of respiratory depression, an important safety concern.3 Medical professionals accepted benzodiazepines enthusiastically at first, increasing their popularity and patient demand. BZDs were prescribed frequently and often long-term for various conditions. Soon they became the pharmacological family par excellence in the treatment of anxiety disorders and so initiating “the benzodiazepine saga”.4 In the mid-to-late 1970s, benzodiazepines became the most commonly prescribed medication in the world, providing treatment for “minor forms” of anxiety. It took 15 years for the researchers to associate benzodiazepines and their effect with their high-affinity receptor complex as the mechanism of action. They did it in 1977 and it was the major
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