G.P. Ellis (9).Pdf

Progress in Medicinal Chemistry 23 This Page Intentionally Left Blank Progress in Medicinal Chemistry 23 Edited by G.P. ELLIS, D.SC., PH.D., F.R.S.C. Department of Applied Chemistry, University of Wales Institute of Science and Technology, P.O.Box 13, Cardif, CFl 3XF, United Kingdom and G.B. WEST, B. PHARM., D.SC., PH.D., F.I.BIOL. Department of Paramedical Sciences, North East London Polytechnic, Romford Road, London, El5 4LZ, United Kingdom 1986 ELSEVIER AMSTERDAM. NEW YORK .OXFORD 0 1986, Elsevier Science Publishers B.V. (Biomedical Division) All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher, Elsevier Science Publishers B.V. (Biomedical Division), P.O. Box 1527, 1000 BM Amsterdam, The Netherlands. Special regulations for readers in the U.S.A: This publication has been registered with the Copyright Clearance Center Inc. (CCC), Salem, Massachusetts. Information can be obtained from the CCC about conditions under which the photocopying of parts of this publication may be made in the USA. All other copyright questions, including photocopying outside of the USA, should be referred to the publisher. ISBN 0-444-80802-7 ISBN Series 0-7204-7400-0 Published by: Elsevier Science Publishers B.V. (Biomedical Division) P.O. Box 21 1 1000 AE Amsterdam The Netherlands Sole distributors for the USA and Canada: Elsevier Science Publishing Company, Inc. 52 Vanderbilt Avenue New York, NY 10017 USA Library of Congress Cataloging in Publication Data Please refer to card number 62-27/2 for this series Printed in The Netherlands Preface We have pleasure in presenting six reviews in this volume, all of which cover important advances in the chemistry and biology of medicinal products. In Chapter 1, structure-activity relationships within a series of a-adrenoceptor antagonists are discussed, particularly as regards their use in the fields of depression, diabetes and hypertension. The latest research into cell surface receptors after introducing radioligand binding is covered in Chapter 2 and a similar theme is continued in Chapter 3 where common structural features of drugs, transmitters and peptides in the central nervous system are evaluated. Chapter 4 covers the biological and chemical aspects of recently-introduced antidepressant drugs. The discovery of acyclovir as a potent and selective anti-herpes agent is described in Chapter 5. Fidally in Chapter 6, the antibiotic sparsomycin is reviewed for the first time in detail. It appears to be an anti-tumour agent af high promise, being an inhibitor of the peptide bond formation step in protein synthesis. Again, we thank our authors for their efforts, the owners of copyright for permission to reproduce material, and the staff of our publishers for their constant help and encouragement. We also wish to thank Mrs. A.E. Bisgood (Department of Computing, UWIST) for assistance in producing the index to this volume. G.P. Ellis December 1985 G.B. West This Page Intentionally Left Blank Contents Preface V 1. Pharmacology and Structure-Activity Relationships of a,-Adreno- ceptor Antagonists 1 R.D. Clark, Ph.D.", A.D. Michel, Ph.D.b, and R.L. Whiting, Ph.D.b "Institute of Organic Chemistry and bInstitute of Pharmacology and Metabolism, Syntex Research, Palo Alto, CA 94304, U.S.A. 2. Radioligand-Receptor Binding in Membrane Receptor Research 41 M. &man-Krian, Ph.D. Department of Pharmacology,Medical Faculty, Vrazov trg 2, University Edvard Kardelj, 61000 Ljubljana, Yugoslavia 3. Common Structural Features of Drugs, Transmitters and Peptides in the Central Nervous System 91 P.R. Andrews, Ph.D. and E.J. Lloyd School of Pharmaceutical Chemistry, Victorian College of Pharmacy Ltd., 381 Royal Parade, Parkville, Victoria, 3052, Australia 4. Recent Progress in the Development of New Antidepressant Drugs 121 S.I. Ankier, Ph.D., F.P.S. Charterhouse Clinical Research Unit, Boundary House, London, EClM 6HR. United Kingdom 5. Chemotherapeutic Agents for Herpesvirus Infections 187 E. De Clercq, M.D., Ph.D." and R.T. Walker, Ph.Db. "Rega Institute for Medical Research, Katholieke Universiteit Leuven. B-3000 Leuven, Belgium and "Department of Chemistry, University of Birmingham, Birmingham BIS 2TT. United Kingdom 6. Chemical and Biological Aspects of Sparsomycin, an Antibiotic from Streptomyces 219 H.C.J. Ottenheijm, Ph.D.", L.A.G.M. van den Broek, M.Sc.", J.P.G. Ballesta, Ph.D.b &d Z. Zylicz, M.D." aDepartment of Organic Chemistry, University of Nijmegen. Toernooi- veld, 6525 ED Nijmegen, The Netherlands, bCentro de Biologia Mole- cular, CSIC and UAM, Canto Blanco, Madrid-28049, Spain, and 'Department of Internal Medicine, Division of Medical Oncology. St. Radboud University Hospital, 6525 GA Nijmegen, The Netherlands Index 269 Author Index (Vols. 1-23) 275 Subject Index (Vols. 1-23) 279 Progress in Medicinal Chemistry - Vol. 23, edited by G.P. Ellis and G.B. West 0 1986, Elsevier Science Publishers, B.V. (Biomedical Division) 1 Pharmacology and Structure-Activity Relationships of a,-Adrenoceptor Antagonists ROBIN D. CLARK, Ph.D.", ANTON D. MICHEL, Ph.D.b and ROGER L. WHITING, Ph.D.b "Institute of Organic Chemistry and bInstitute of Pharmacology and Metabolism, Syntex Research, Palo Alto, CA 94304, U.S.A. INTRODUCTION 2 CLASSIFICATION OF Q-ADRENOCEPTORS 2 PHARMACOLOGICAL EVALUATION OF Q-ADRENOCEPTOR ANTA- GONISTS - 3 POTENTIAL CLINICAL USES OF Q-ADRENOCEPTOR ANTAGONISTS 6 Depression 7 Diabetes 8 Obesity 8 Hypertension 8 Platelet dysfunctions 9 Impotence 9 a-ADRENOCEPTOR ANTAGONISTS 9 Yohimbine and its Stereoisomers and Analogues 9 Mianserin, CGS-7525A and Related Compounds 13 Benzodioxans - Idazoxan, Imiloxan and Related Compourids 16 2-Sulphonamidobenzoquinolizines 20 4-Chloro-2-(2-imidazolin-2-ylamino)isoindoline(BDF-6143) 21 2-[2-(4,5-Dihydro-lH-imidazol-2-yl)-l-phenylethyl]pyridine(DG-5 128) 22 a-Aryloxybenzyl morpholines 24 Piperazinylimidazo[1 ,2-a]pyrazines, pyridinylpiperazines and pyridinyltetrahydro- pyridines 24 1,2,3,4-TetrahydroisoquinoIines 26 2,3,4,5-Tetrahydro- 1H-3-benzazepines 27 Miscellaneous compounds 30 2 c+-ADRENOCEPTOR ANTAGONISTS MODELS OF THE a-ADRENOCEPTOR 32 CONCLUSION 33 ACKNOWLEDGEMENTS 33 REFERENCES 34 INTRODUCTION Since the initial proposal by Ahlquist in 1948 that adrenoceptors (adrenergic receptors) be classified into a- and /?-adrenoceptorsubtypes [ 11, a great deal of work has been carried out which has resulted in a further subclassification of these adrenoceptors. Thus, the /?-adrenoceptorhas been subclassified into PI- and /?,-adrenoceptors and the a-adrenoceptor has been subclassified into al- and g-adrenoceptors. Development of selective agonists and antagonists for these adrenoceptor subtypes has led to a number of important clinical agents. For example, the clinical efficacy of 8,-adrenoceptor antagonists in the treatrgent of cardiovascular disorders and of /?,-adrenoceptor agonists for broncgial asthma is well established. Agents which act predominantly at a-adrenoceptors include a,-agonists as decongestants, a,-adrenoceptor antagonists, such as prazosin, for hypertension, and g-adrenoceptor agonists such as clonidine, also for the treatment of hypertension. More recently, a substan- tial amount of effort has been devoted to the discovery of selective g-adrenoceptor antagonists in the hope of obtaining similarly useful clinical entities. Several recent reviews cover the classification, pharmacology, and possible clinical utilities of a,-adrenoceptor antagonists [ 2-61 and therefore these areas will be only briefly mentioned here. This review will instead concentrate on the a-adrenoceptor antagonist compounds which have been reported and the structure-activity relationships (SAR) which are available on the various series of antagonists. We have not attempted to cover the chemical synthesis of these agents, and for this information the reader is referred to the original publica- tions. CLASSIFICATION OF a,-ADRENOCEPTORS The a-adrenoceptor was originally subdivided on an anatomical basis into pre- and postsynaptic subtypes. It has subsequently been pointed out that the terms pre- and postjunctional are more encompassing [7] and these will be used in R.D. CLARK, A.D. MICHEL AND R.L. WHITING 3 this review. This original classification followed the demonstration of prejunctional a-adrenoceptors that inhibited neurotransmitter release in a wide range of tissues from several species [8-111. The terms al- and Q-adrenoceptors [ 121 were subsequently adopted to describe post- and prejunctional adrenoceptors, respectively [ 131. However, the demonstration that g-adrenoceptors occur postjunctionally in human platelets [ 141, human adipocytes [ 151 and vascular smooth muscle [ 161 has led to the formulation of alternative methods of subclassification. An early proposal for a functional classification system which designated a,- and cyadrenoceptors as excitatory and inhibitory, respectively [ 171, has also required modification since inhibitory prejunctional a,-adrenoceptors [ 18-20] and excitatory and inhibitory postjunctional g- adrenoceptors [7, 161 have been described. More recently, a subclassification of a-adrenoceptors based on the bio- chemical responses initiated following receptor stimulation has been proposed [ 2 11. According to this method of subclassification,those a-adrenoceptors that stimulate the turnover of phosphatidylinositol are termed a,-adrenoceptors, while

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