Receptor Data for Biological Experiments: A Guide to Drug Selectivity 0137674503, 9780137674503

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ELLIS HORWOOD SERIES IN PHARMACOLOGICAL SCIENCES

RECEPTOR DATA FOR BIOLOGICAL EXPERIMENTS a guide to drug selectivity H. N. Doods and J. C. A. van Meel

RECEPTOR DATA FOR BIOLOGICAL EXPERIMENTS A Guide to Drug Selectivity

ELLIS HORWOOD SERIES IN PHARMACEUTICAL TECHNOLOGY Editor: Professor M. H. RUBINSTEIN, School of Health Sciences, Liverpool Polytechnic UNDERSTANDING EXPERIMENTAL DESIGN AND INTERPRETATION IN PHARMACEUTICS N. A. Armstrong & K. C. James MICROBIAL QUALITY ASSURANCE IN PHARMACEUTICALS, COSMETICS AND TOILETRIES Edited by S. Bloomfield el at. PHARMACEUTICAL PRODUCT LICENSING: Requirements for Europe Edited by A. C. Cartwright & B. R. Matthews DRUG DISCOVERY TECHNOLOGIES C. Clark & W. H. Moos PHARMACEUTICAL PRODUCTION FACILITIES: Design and Applications G. Cole PHARMACEUTICAL TABLET AND PELLET COATING G. Cole THE PHARMACY AND PHARMACOTHERAPY OF ASTHMA Edited by P. F. D'Arcy & J. C. McElnay GUIDE TO MICROBIOLOGICAL CONTROL IN PHARMACEUTICALS Edited by S. P. Dcnyer & R. M. Baird RECEPTOR DATA FOR BIOLOGICAL EXPERIMENTS: A Guide to Drug Selectivity Edited by H. N. Doods and J. C. A. van Meel PHARMACEUTICAL THERMAL ANALYSIS: Techniques and Applications J. L. Ford and P. Timmins PHYSICO-CHEMICAL PROPERTIES OF DRUGS: A Handbook for Pharmaceutical Scientists P. Gould DRUG DELIVERY TO THE GASTROINTESTINAL TRACT Edited by J. G. Hardy, S. S. Davis and C. G. Wilson POLYPEPTIDE AND PROTEIN DRUGS: Production, Characterization and Formulation Edited by R. C, Hider and D, Barlow HANDBOOK OF PHARMACOKINETICS: Toxicity Assessment of Chemicals J. P. Labaune TABLET MACHINE INSTRUMENTATION IN PHARMACEUTICS: Principles and Practice P. Ridgway Watt PHARMACEUTICAL CHEMISTRY, Volume 1 Drug Synthesis H. J. Roth el al. PHARMACEUTICAL CHEMISTRY, Volume 2 Drug Analysis H. J. Roth el al. PHARMACEUTICAL TECHNOLOGY: Controlled Drug Release, Volume 1 Edited by M. H. Rubinstein PHARMACEUTICAL TECHNOLOGY: Controlled Drug Release, Volume 2* Edited by M. H. Rubinstein PHARMACEUTICAL TECHNOLOGY: Tableting Technology, Volume 1 Edited by M. H. Rubinstein PHARMACEUTICAL TECHNOLOGY: Tableting Technology, Volume 2* Edited by M. H. Rubinstein PHARMACEUTICAL TECHNOLOGY: Drug Stability Edited by M. H. Rubinstein PHARMACEUTICAL TECHNOLOGY: Drug Targeting* Edited by M. H. Rubinstein UNDERSTANDING ANTIBACTERIAL ACTION AND RESISTANCE A. D. Russell and I. Chopra RADIOPHARMACEUTICALS USING RADIOACTIVE COMPOUNDS IN PHARMACEUTICS AND MEDICINE Edited by A. Theobald PHARMACEUTICAL PREFORMULATION: The Physicochemical Properties of Drug Substances J. I. Wells PHYSIOLOGICAL PHARMACEUTICS: Biological Barriers to Drug Absorption C. G. Wilson & N. Washington PHARMACOKINETIC MODELLING USING STELLA ON THE APPLE™ MACINTOSH™ C. Washington, N. Washington & C, Wilson * In preparation

RECEPTOR DATA TOR BIOLOGICAL EXPERIMENTS A Guide to Drug Selectivity LIBRARY Editors

2 5 1992

H. N. DOODS J. C. A. VAN MEEL

National Institutes o • ea

Department of Pharmacological Research Dr Karl Thomae GmbH, 7950 Biberach 1, Germany

ELLIS HORWOOD NEW YORK

LONDON

TORONTO

SYDNEY

TOKYO

SINGAPORE

3ol^l P13

mi

A

First published in 1991 by

ELLIS HORWOOD LIMITED Market Cross House, Cooper Street, Chichester, West Sussex, P019 1EB, England A division of Simon & Schuster International Group A Paramount Communications Company

© Ellis Horwood Limited,

1991

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 permission, in writing, of the publisher Every effort has been made to trace all copyright holders, but if any have been inadvertently overlooked, the publishers will be pleased to make the necessary arrangements at the earliest opportunity. Typeset in Times by Ellis Horwood Limited Printed and bound in Great Britain by Bookcraft Limited, Midsomer Norton, Avon

British Library Cataloguing in Publication Data Doods, H. N. Receptor data for biological experiments. — (Ellis Horwood series in pharmaceutical technology) I. Title II. van Meel, J.C.A. III. Series 574.19 ISBN 0-13-767450-3

Library of Congress Cataloging-in-Publication Data Doods, H. N. (Henri N.). 1958Receptor data for biological experiments : a guide to drug selectivity / H. N. Doods, J. C. A. van Meel. p. cm. — (Ellis Horwood series in pharmacological sciences) Includes bibliographical references and index. ISBN 0-13-767450-3 I. Drug receptors. 2. Cell receptors. I. Meel, J. C. A. van (Jacques C. A.). 1949- . II. Title. III. Series. [DNLM: 1. Drugs — metabolism. 2. Pharmacology. 3. Receptors. Drug — drug effects. QV 38 D691r] RM301.41.D66 1991 615'.7-dc20 DNLM/DLC 91-20822 for Library of Congress CIP

5

Table of contents

Foreword.11 1.

a-ADRENERGIC RECEPTORS.13 J. C. McGrath, C. M. Brown and V. G. Wilson Institute of Physiology, University of Glasgow, Glasgow G13 8QQ, UK

2.

p-ADRENERGIC RECEPTORS.19 M. C. Michel Department of Medicine, University of Essen, 4300 Essen 1, Germany

3.

NICOTINIC RECEPTORS.23 I. Wessler Department of Pharmacology, University of Mainz, Obere Zahlbacher Str. 67, 6500 Mainz, Germany

4.

MUSCARINIC RECEPTORS..31 H. N. Doods Department of Pharmacology, Dr K. Thomae GmbH, PO Box 1755, 7950 Biberach 1, Germany

5.

5-HYDROXYTRYPTAMINE RECEPTORS.35 D. Hoyer and J. R. Fozard Preclinical Research, SANDOZ Pharma Ltd, CH-4002 Basle, Switzerland

6.

DOPAMINE RECEPTORS.42 P. Seeman Departments of Pharmacology and Psychiatry, Medical Sciences Building, University of Toronto, Toronto, Canada M5S 1A8

Table of contents

6

7.

HISTAMINERGIC RECEPTORS.47 R. Leurs and H. Timmerman Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands

8.

PURINERGIC RECEPTORS. C. H. V. Hoyle and G. Burnstock

54

Department of Anatomy and Developmental Biology, and Centre for Neuro¬ science, University College London, Gower Street, London WC1E 6BT, UK

9.

VASOPRESSIN RECEPTORS.62 L. B. Kinter, S. Caltabiano and W. F. Huffman Departments of Investigative Toxicology and Peptide Chemistry, SmithKline Beecham Pharmaceuticals, PO Box 1539, King of Prussia, PA, USA

10.

BRADYKININ RECEPTORS.69 R. Plevin and P. J. Owen Department of Biochemistry, University of Glasgow, Glasgow G12 8QQ, UK; and Department of Pharmacology, University of Leicester, Medical Sciences Building, PO Box 138, Leicester, UK

11.

ENDOTHELIN RECEPTORS.73 J. P. Huggins and R. C. Miller Merrell Dow Research Institute, 16, rue d’Ankara, BP 447 R/9, 67009 Strasbourg, France

12.

ENDOTHELIUM-DERIVED RELAXING FACTOR (EDRF).78 J. A. Smith and M. J. Lewis Departments of Cardiology, Pharmacology and Therapeutics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK

13.

ATRIAL NATRIURETIC FACTOR RECEPTORS.82 R. M. Snajdar and T. Inagami Department of Biochemistry, Vanderbilt University Medical School, Nashville, TN, USA

14.

INHIBITORS OF ATRIAL NATRIURETIC FACTOR DEGRADATION

.87

R. J. Winquist Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877, USA

15.

NEUROPEPTIDE Y/PEPTIDE YY RECEPTORS..92 R. E. Lang and H. N. Doods Institut fur Normale und Pathologische Physiologie, Philipps-Universitat Marburg, Deutschhausstr. 2, 3550 Marburg, Germany and Department of Pharmacology, Dr K. Thomae GmbH, PO Box 1755, 7950 Biberach 1, Germany

Table of contents

7

16. ANGIOTENSIN II RECEPTORS.96 P. B. M. W. M. Timmermans, W. F. Herblin, R. J. Ardecky, D. J. Carini, J. V. Duncia, P. C. Wong, R. R. Wexler, R. D. Smith, A. L. Johnson and A. T. Chiu The Du Pont Merck Pharmaceutical Company, PO Box 80400, Wilmington, DE 19880-0400, USA

17. CONVERTING ENZYME INHIBITORS.100 P. Gohlke and T. Unger Department of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 6900 Heidelberg, Germany

18. RENIN INHIBITORS.103 J. M. Wood, F. Cumin and J. Maibaum Cardiovascular Research Department, Ciba-Geigy Ltd, Basle, Switzerland CH-4002

19.

THROMBIN.

... 107

T. H. Muller and W. G. Eisert Department of Pharmacology, Dr K. Thomae GmbH, POB 1755, 7950 Biberach 1, Germany

20. FIBRINOGEN RECEPTORS.112 T. H. Muller and F. Himmelsbach Pharmaceutical Research, Dr K. Thomae GmbH, POB 1755,7950Biberach 1, Germany

21. PLATELET-ACTIVATING FACTOR RECEPTORS.118 H. O. Heuer Department of Pharmacology, Boehringer Ingelheim KG, 6507 Ingelheim, Germany

22. VASOACTIVE INTESTINAL PEPTIDE RECEPTORS.122 G. Velicilebi, S. A. Provow and S. Patthi Salk Institute, Biotechnology/Industrial Associates Inc. (SIBIA), 505 Coast Blvd S., La Jolla, CA 92037, USA

23. RECEPTORS FOR NEUROKININS, CHOLECYSTOKININ, BOMBESIN AND RELATED PEPTIDES.131 D. Regoli and N. Rouissi Department of Pharmacology, Medical School, University of Sherbrooke, Sherbrooke, Canada I1H 5N4

Table of contents

8

24. CALCITONIN AND CALCITONIN GENE-RELATED PEPTIDE RECEPTORS.a..138 S. J. Wimalawansa and I. MacIntyre Department of Medicine and Endocrinology, Royal Postgraduate Medical School, Du Cane Road, London W12 ONN, UK

25. CYCLIC AMP- AND CYCLIC GMP-SPECIFIC PHOSPHODIESTERASES.145 R. E. Weishaar and T. D’Ambra Divisions of Biological Research and Chemistry, Coromed Inc., Rensselaer Technology Park, Troy, New York 12180, USA

26. PROSTANOID RECEPTORS.151 R. A. Coleman Department of Peripheral Pharmacology, Glaxo Group Research Ltd, Park Road, Ware, Hertfordshire SG12 ODP, UK

27. LEUCOTRIENES: 5-LIPOXYGENASE METABOLITES OF ARACHIDONIC ACID.156 L. G. Letts Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals Inc., 90 East Ridge, Ridgefield, CT 06877, USA

28. PROTEIN KINASES.161 P. D. Davis and J. S. Nixon Roche Products Ltd, PO Box 8, Welwyn Garden City, Hertfordshire AL7 3AY, UK

29. CALMODULIN ANTAGONISTS.169 J. Norman Department of Pharmacology, The Squibb Institute for Medical Research, PO Box 4000, Princeton, NJ, USA

30. SARCOPLASMIC RETICULUM Ca2+ UPTAKE AND RELEASE.175 J. S. Smith Department of Pharmacology, Merck Sharp & Dohme Research Labs, West Point, PA 19486, USA

31. CALCIUM CHANNEL MODULATORS...181 B. Wilffert, D. Wilhelm, D. Wermelskirchen and T. Peters Janssen Research Foundation, PO Box 210440, 4040 Neuss 21, Germany

Table of contents

32.

9

SODIUM CHANNEL MODULATORS.190 G. Scholtysik Universitat Bern, Veterinar-pharmakologisch Institut, Langass-Strasse 124, CH-3012 Bern, Switzerland

33.

POTASSIUM CHANNEL MODULATORS.194 G. Edwards and A. H. Weston Smooth Muscle Research Group, Department of Physiological Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK

34.

SODIUM COUNTERTRANSPORT MECHANISMS.209 G. J. Kaczorowski Department of Membrane Biochemistry and Biophysics, Merck Institute for Therapeutic Research, PO Box 2000, Rahway, NJ 07065, USA

35.

H+, K+-ATPase INHIBITORS.215 J. Fryklund, P. Lorentzon and C. Briving Department of Biology, Gastrointestinal Research, AB Hassle, S-431 83 Molndal, Sweden

36. OPOID RECEPTORS.220 J. Traynor Department of Chemistry, University of Technology, Loughborough, Leicestershire, LE11 3TU, UK

\J 37.

GABAa AND BENZODIAZEPINE RECEPTORS.225 D. J. Nutt Reckitt & Colman Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK

^38.

GABAb RECEPTORS.230 A. L. Hudson Reckett & Colman Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK

EXCITATORY AMINO ACID RECEPTORS.234 E. W. G. M. Boddeke and P. Herrling Sandoz Preclinical Research, SANDOZ Pharma Ltd, CH-4002 Basle, Switzerland

40.

CYTOKINE RECEPTORS.241 H. Holtmann, M. Szamel and K. Resch Institute of Molecular Pharmacology, Medical School 3000, Hannover, Germany

10

41.

Table of contents

STEROID HORMONE RECEPTORS.247 K. H. Fritzemeier and D. Henderson

^ Research Laboratories of Schering AG, Miillerstrasse 170-178, 1000 Berlin 65, Germany i

42.

G-PROTEINS, RECEPTORS AND EFFECTORS.269 J. Abramowitz and L. Birnbaumer Departments of Medicine, Cell Biology, Molecular Physiology and Biophysics, and Division of Neurosciences, Baylor College of Medicine, Houston, TX 77030, USA

Index

279

11

Foreword

The idea to publish a comprehensive overview of a number of receptor/enzyme systems and selectivity of compounds has been discussed for many years in our department. The rate at which research is advancing is so rapid that we all are regularly confronted with questions such as ‘How many receptors do actually exist?’, ‘Where are these receptors located?’ or ‘What compounds should I use?’ for those topics where we are not experts. As researchers we like to use accepted standards as well as optimal tools for our experiments. However, finding the right literature is frequently a tedious and long-winded job. Therefore we thought that a volume like this may save time and improve the quality of our work. So, this edition is intended for those colleagues who do not have time to spend many hours in the library and who do not want to wait several days for a literature search and selection of relevant information. This has been done for you by the experts in the fields! We are aware that this volume is certainly not complete. Our most difficult task has been that of selection. However, we think that we have covered such a wide range that the majority of readers will be satisfied. We are greatly indebted to all the authors who contributed to this volume and we are proud to have the support of such a distinguished group of highly qualified researchers from industry and university. Finally, we would like to thank the publishers for their cooperation and understanding during the preparation of this volume. February 1991

H. N. Doods J. C. A. van Meel

13

a-Adrenergic receptors J. C. McGrath, C. M. Brown and V. G. Wilson Institute of Physiology, University of Glasgow, Glasgow G13 8QQ, UK

SUBCLASSIFICATION On a functional basis a-adrenoceptors can be defined as receptors at which adrena¬ line and noradrenaline are agonists, phentolamine is an antagonist (pA2 7-9)and propranolol is not an antagonist (pA28) is the ubiquitous definition for al5 but is now well supported by other high-affinity, selective antagonist/ligands; within dj, 5-methyl urapidil separates a high-affinity site (pA2~9) from a low-affinity site (pA2>7.5) with several supporters; within the same d! subset, affinities for prazosin and yohimbine divide the set into two alternative subsets, djH and d1L (high and low), which do not correspond to d1A and d1B. Similarly d2 can be defined by affinity for yohimbine (pA2>7) (or its stereoisomer rauwolscine) with high-affinity supporters (and after exclusion of 5-hydroxytryptamine (5-HT) sites); within this d2 subset (binding only), prazosin separates a moderate-affinity site (pKj—7.0-7.5) and a very low-affinity site (pKt^6) with several supporters. Neither yohimbines nor imidazoline ligands bind exclusively to adrenoceptors, necessitating a broad spread of ligands in characterization studies. Molecular cloning demonstrates the existence of 3 ‘d-adrenergic receptor’ genes. These receptors have been designated oq, d2-C4 and d2-C10. The d! receptor is

14

a-Adrenergic receptors

[Ch. 1

coupled by a PTX(=pertussis toxin)-resistant G-protein to phospholipase C (primar¬ ily); a2-C4 and a2-C10 are coupled by a PTX-sensitive G-protein to inhibit adenylyl cyclase (primarily) and to phospholipase C. Correlation with functional subclassifi¬ cation is incomplete; a2-C10 corresponding to a2A; a! to a1A [1-3]; classification of aC4 remains to be seen. 4

LOCALIZATION Most tissues contain more than one receptor type but homogeneous exceptions to this allow clarity of definition and purification. In general ax are less common than a2 on peripheral nerves and a2-mediated smooth muscle contraction is less easy to demonstrate under standard in vitro conditions than is dj. This allows simple bioassay of agonists and antagonists for the two major subtypes at post (aj) and pre (a2) junctional sites, e.g. both in vitro and in vivo (pithed model) for rat anococcygeus (post a\), atria (chronotropic (pre a2)) and vas deferens (pre a2); similarly post a2 can be assayed on pithed rat/rabbit blood pressure or isolated rabbit ear vein [4-9].

SOURCES A. B. C. D. E. F. G. H.

Commercially available. Pfizer, Sandwich, Kent, UK. Yamanuchi, Tokyo, Japan. Byk Gulden, Konstanz, Germany. Syntex, Palo Alto, USA. Beechams, Surrey, UK. Chinoin, Budapest, Hungary. Thomae GmbH, Biberach, Germany.

REVIEW ARTICLES Starke, K. 1987. Presynaptic a-autoceptors. Rev. Physiol. Biochem. Pharmacol., 107,74-146. Ruffolo, R. R. Jr (ed.) 1987. The alpha-1 adrenergic receptors. Humana Press, New Jersey. Bylund, B. D. 1988. Subtypes of alpha 2-adrenoceptors: pharmacological and molecular biological evidence converge. Trends Pharmacol. Sci., 9, 356-361. Minneman, K. P. 1988. arAdrenergic receptor sub-types, inositol phosphates and sources of cell Ca2+. Pharmacol. Rev., 40, 87-120. Limbird, L. E. (ed.) 1988. The alpha-2 adrenergic receptors. Humana Press, New Jersey. Docherty, J. R. 1989. The pharmacology of a! and a2 adrenoceptors: evidence for and against a further sub-division. Pharmacol. Ther., 44, 241-284. McGrath, J. C., Brown, C. M. and Wilson, V. G. 1989. Alpha-adrenoceptors: a critical review. Med. Res. Rev., 9, 407-533.

REFERENCES [1] [2] [3] [4]

Cotecchia, S. et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 7159. Cotecchia, S. et al., J. Biol. Chem., 1990, 265, 63. Bylund, D. B., Trends Pharmacol. Sci., 1988, 9, 356. Drew, G. M., Eur. J. Pharmacol., 1976, 36, 313.

Ch. 1]

a-Adrenergic receptors

15

[5] Docherty, J. R. and McGrath, J. C., Naunyn-Schmiedebergs Arch. Pharmacol. 1979, 309, 225. [6] Docherty, J. R. and McGrath, J. C., Naunyn-Schmiedebergs Arch. Pharmacol. 1980, 312,107. [7] McGrath, J. C., Br. J. Pharmacol. 1984, 82, 769. [8] Bulloch, J. M., Br. J. Pharmacol. 1987, 91, 457. [9] Daly, C. J. Br. J. Pharmacol. 1988, 94, 1085. [10] Wikberg, J. E. S., Nature, 1978, 273, 164. [11] Han, C. etal., Nature, 1987, 329, 333. [12] Boer, R. etal., Eur. J. Pharmacol., 1989, 172, 131. [13] Gross, G. et al., Br. J. Pharmacol., 1989, 98, 698P. [14] Morrow, A. L. and Creese, I., Mol. Pharmacol., 1986, 29, 321. [15] Hanft, G. and Gross, G., Br. J. Pharmacol., 1989, 98, 652P. [16] Michel, A. D. et al., Br. J. Pharmacol., 1989, 98, 883. [17] Bylund, D. B., Mol. Pharmacol., 1982, 21, 27. [18] Snavely, M. D. and Insel, P. A., Mol. Pharmacol., 1982, 22, 532. [19] Barnes, P. J., Clin, Sci. Mol. Med., 1988, 58, 457. [20] Flavahan, N. A. and Vanhoutte, P. M., Trends Pharmacol. Sci., 1986, 7, 347. [21] Muramatsu, I. etal., Br. J. Pharmacol., 1990, 99, 197. [22] Drew, G. M., Eur. J. Pharmacol., 1977, 42, 123. [23] Bylund, D. B., Pharmacol. Biochem. Behav., 1985, 22, 835. [24] Brown, C. M. et al., Br. J. Pharmacol., 1990, 99, 481. [25] Petrash, A. C. and Bylund, D. B., Life Sci., 1986, 38, 2129. [26] Motomura, S. et al., J. Hypertension, 1989, 7, 550. [27] Cheung, Y.-D. et al., Eur. J. Pharmacol., 1982, 84, 79. [28] Michel, A. D. et al., Br. J. Pharmacol., 1989, 98, 890. [29] Bylund, D. B. etal.,J. Pharmacol. Exp. Ther., 1988, 245, 600. [30] Bylund, D. B. and Ray-Prenger, C.,J. Pharmacol. Exp. Ther., 1989, 251, 640. [31] Burns, T. W. et al.,J. Clin. Invest., 1981, 67, 467. [32] MacKinnon, A. C. et al., Br. J. Pharmacol., 1989, 98, 1143. [33] Latipour, J. etal.,J. Pharmacol. Exp. Ther., 1982, 223, 606. [34] Ruffolo, R. R. et al., Naunyn-Schmiedebergs Arch. Pharmacol., 1988, 336, 415. [35] Daiguji, M. et al., Life Sci., 1981, 28, 2705. [36] Brown, C. M. et al., Br. J. Pharmacol., 1988, 93, 417. [37] Cambridge, D., Eur. J. Pharmacol., 1981, 72, 413. [38] Honda, K. et al., Naunyn Schmiedebergs Arch. Pharmacol., 1987, 336, 295. [39] Gross, G. et al., Eur. J. Pharmacol., 1988, 151, 333. [40] Clark, R. D. et al., Br. J. Pharmacol., 1990, 99 Proc. Suppl., 123P. [41] Cheung, Y-D. et al., Biochem. Pharmacol., 1984, 33, 1566. [42] Vizi, E. S. et al.,J. Pharmacol. Exp. Ther., 1986, 238, 701. [43] Young, P. et al., Eur. J. Pharmacol., 1989, 168, 381. [44] Regan, J. W. et al., Proc. Natl. Acad. Sci., USA, 1988, 85, 6301.

[Ch. 1

a-Adrenergic receptors

16

6 i

OC ligand

Phentolamine

CXI ligands

Prazosin YM 12617 5me-urapidil Corynanthine Indoramin

OC2 ligands

Sub-type specific ligands

7 1

i

8 1

i

9 10 11 12 'I

■

)

□ ai ^7 A O B L:H ooundary

H a2 T

Oxymetazoline WB 4101

1 '

\

3

4

m ■ i ■ i ■ ) n ■ i ' i 1 i 5

6

7

8

9 10 11 12

pA2 or pD2 or pK, Criteria for sub-sets functional responses ligands only

A

• B

Yohimbine Rauwolscine WY 26703 CH 38083 BDF 6143 Imiloxan Idazoxan RS 15385 197

phcntolaminc BSl

a

Fig. 1 —Subclassification of a-adrenoceptors by functional ligands.

Ch. 1]

a-Adrenergic receptors

17

Table 1 — Biological effects Tissue

Species

Response biank=binding data

Ref.

a, (undivided) Aorta Anococcygeus

Guinea-pig Rat

Vascular s.m. contraction Non-vascular s.m. contraction

10 7

Vas deferens

Rat

S.m. contraction, DHPsensitive Ca2+ channels (L channels?)

11,12

Cerebral cortex or hippocampus

Guinea-pig, rat human

13-15

Heart

Rat

15

Homogeneous tissues Submaxillary gland Submandibular gland

Rat Rat

16 17

alA

aIB

Vas deferens Cerebral cortex or hippocampus Heart

Rat Guinea-pig, rat human Rat

Homogeneous tissues Liver Kidney Lung

Rat Rat Human

DHP-resistant contraction

11 13-15 15 11,16 18 19

alll aIL

Various blood vessels

Rabbit

S.m. contraction

20,21

a2 (undivided) Vas deferens Ileum

Rat Guinea-pig

22 10

Ear vein

Rabbit

Inhib. neurotrans. sympathetic Inhib. neurotrans. parasympathetic Vascular s.m. contraction

a2A (a2-C10; ref. [46]) Cerebrum Caudate, kidney, myometrium

Rat, human Human

23-25 26

Human Rabbit Human cell line

27 28 29 30 31 32

Homogeneous tissues Platelet Spleen HT 29 (clonic adrenocarcinoma) Adipocyte

Human Hamster

cAMP Glycerol release

9

a2B

Cerebrum

Caudate, kidney, Myometrium Homogeneous tissues Lung Kidney NG-108xGlioma Hybrid neuroblastoma a2 (pre/post-junctional selectivity) DHP=dihydropyridine.

Human Human

23 24 25 26

Neonate rat Rat Rat cell line cAMP

33 28 29 30

Rat/guinea-pig

34

Rat

[Ch. 1

a-Adrenergic receptors

18

Table 2 — Selective drugs A

Compound (source)

Selectivity

Affinity/potency pKj or pA2 ■i

Agonists Noradrenaline (A),

a1A>aiB a2B>a2A

Adrenaline (A)

alA>alB a2A = a2B

Phenylephrine (A) UK 14304 (B)

ai>a2 a2>a!

v

Ref.

(* or pD2)

6.7>5.0 7.14>6.44 7.2>5.4 7.1=7.0 5.5-7.5*>(^5.5*) 8.05.3*

14 35 14 33 36,37 37

10.1>7.3>6.0 (>9.5)>(8.0-9.0) 10.3>8.9^>6.0 10.3>7.5 9.2>7.4 9.25>8.14

12,13 20,21 15,38 12 39 16

10.1^5.7 7.8>6.0 (>6.5)>(5.5 8.0>5.7 8.8>6.8 7.2>5.3 8.8>6.7 7.3>5.5 8.9>7.0

40 41 20,21 42 41 43 24 29 28 43

Antagonists ttj

Prazosin (A)

ai>a2B>a2A alH>alL

YM 12617 (C) (+)-Niguldipine (D) 5-Methyl-urapidil (D) Spiperone (A)

aiA>aiB^a2

RS-15385-197 (E) Yohimbine (A)

a2>a.\ a2>aj

aiA>aiB aiA>aiB alB>alA

a2

alH>alL

CH38083 (F) Idazoxan (A) BRL 44408 (G) Methysergide (A) ARC 239 (H) Imiloxan (E) BRL 41992 (G)

a2^>a! a2>at a2A>a2B a2B>a2A a2B>a2A a2B>a2A a2B>a2A

Subtype specific ligands ( .e. specific for A v. B but not 1 v. 2) Oxymetazoline (A) 8.1>6.6 a2A>a2B 8.9>6.6 alA>alB WB4101 (A) 9 >7-8 a2A>a2B 9.2>6.0 alA>alB

24 15 29,16 11,14

19

2 P-Adrenergic receptors Martin C. Michel Department of Medicine, University of Essen, 4300 Essen 1, Germany

SUBCLASSIFICATION Historically P-adrenergic receptors have been classified into a P! and a p2 subtype, which are distinguished by the agonist order of potency isoproterenol> adrenaline-noradrenaline for pr and isoproterenol>adrenaline>noradrenaline for p2-adrenergic receptors [1], This subclassification was confirmed by the deve¬ lopment of highly subtype-selective antagonists; today the most selective antagonists available are bisoprolol and CGP 20,712A (P^ and ICI 118,551 (p2). The two receptor subtypes have beeen cloned in various species including man and the genomic counterparts of these cDNAs are located on separate human chromosomes [2]. Additionally, it has been found that the P-adrenergic receptors mediating lipolysis and gut motility are atypical (e.g. have very low affinity for standard antagonists such as propranolol) and a third cDNA has been cloned which encodes a P-adrenergic receptor sharing many similarities with the pharmacologically defined atypical p-adrenergic receptors [3,4]. Besides full agonists and pure antagonists, compounds with various degrees of intrinsic efficacy at P-adrenergic receptors have been identified. Those with a relatively high intrinsic efficacy are usually termed partial agonists whereas those with a small intrinsic efficacy are frequently called antagonists with intrinsic sympath¬ omimetic activity (ISA) [5].

LOCATION AND FUNCTION Whereas the original subclassificattion of P-adrenergic receptors assumed a high degree of tissue specificity, it is now clear that pr and p2-adrenergic receptors coexist in most tissues whereby one subtype usually dominates. Cardiac P-adrenergic receptors are predominantly of the P] subtype (^70% in atria and 80% in ventricles of the human heart) and mediate positive inotropic,

P-Adrenergic receptors

20

[Ch. 2

chronotropic, dromotropic and bathmotropic effects; p2-adrenergic receptors have been convincingly demonstrated in the heart of nearly all species including man but their physiological role is only poorly understood. p2-Adrenergic receptors are involved in the positive chronotropic effects of p-agonists in right atria from rats, guinea-pigs, cats, dogs and humans, but not in those of rabbits. Additionally, in the human heart p2-adrenergic receptors may be involved in positive inotropic effects of some P-agonists [6,7]. Vascular P-adrenergic receptors mediate vasodilation and are mainly of the p2 subtype, although pradrenergic receptors may prevail in some vascular beds (e.g. some coronary arteries) [8]. Renal P-adrenergic receptors are mainly of the Pi subtype. Some renal P-receptors are found in the juxtaglomerular zone and enhance renin release (most species via pr but in rabbit via p2-receptors), but the majority of renal P-adrenergic receptors are located on tubular cells; the function of tubular P-adrenergic receptors is still unclear [9]. Pulmonary P-adrenergic receptors mediate bronchorelaxation and in most spe¬ cies including man are mainly of the p2 subtype but are of the P, subtype in rabbits [10]. It should be noted that some of the p2-receptors found in lung homogenates are not derived from bronchial smooth muscle but rather from macrophages and other leucocytes (see below). Hepatic P-adrenergic receptors are predominantly of the p2 subtype and mediate glycogenolysis and gluconeogenesis [8]. Skeletal muscle also contains P-adrenergic receptors which are mainly of the p2 subtype and are involved in the regulation of cell metabolism [8]. Leucocytes and other blood cells contain a homogeneous population of P2-adrenergic receptors (in mammals) which generally mediate inhibition of the function of the respective leucocyte type such as inhibition of enzyme release, cytokine production, antibody generation and proliferation [11], Adipocytes and smooth muscle cells of the gut contain various types of p-adrenergic receptors but the subtype mediating lipolysis and gut motility appears to be atypical, i.e. neither pj nor p2. Presynaptic P-adrenergic receptors are mainly of the p2 subtype and facilitate transmitter release; evidence for presynaptic prreceptors has been presented in some model systems. In the brain postsynaptic p-adrenergic receptors exist and are believed to be involved in the regulation of various physiological processes. Additionally, it should be mentioned that p2-adrenergic receptors can mediate insulin release and hypokalaemia. SOURCES A. B. C. D. E. F.

Commercially available. Personal synthesis necessary. Eli Lilly & Co, Indianapolis, IN., USA. Imperial Chemical Industries Ltd, Macclesfield, Cheshire, UK. Otsuka Pharmaceuticals, Tokushima, Japan. William H. Rorer Inc., Fort Washington, PA., USA.

Ch. 2] G. H. I. J.

p-Adrenergic receptors

21

AB Hassle, Molndal, Sweden. Ciba Geigy, Basel, Switzerland. Synthelabo, Paris, France. E. Merck, Darmstadt, Germany.

REVIEWS a. O.-E. Brodde, 1987. Cardiac beta-adrenergic receptors. ISI Atlas Sci. Pharmacology, 1, 107-112. b. C. R. Jones, P. Molenaar and R. J. Summers, 1989. New views of human cardiac P-adrenoceptors. J. Mol. Cell Cardiol., 21, 519-535. c. O.-E. Brodde, 1989. P-Adrenoceptors, in: Receptor pharmacology and function, M. Williams et al. (eds), Marcel Dekker, New York, pp. 207-255.

REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]

[21] [22] [23] [24] [25]

Lands, A. M. et al.. Nature, 1967, 214, 597. Yang-Feng, T. L. etal., Proc. Natl. Acad. Sci. USA, 1990, 87, 1516. Emorine, L. J. etal., Science, 1989, 245, 1118. Zaagsma, J. and Nahorski, S. R. Trends Pharmacol. Sci., 1990, 1, 3. Jasper, J. R., Michel, M. C. and Insel, P. A., Mol. Pharmacol., 1990, 37, 44. Brodde, O.-E., IS I Atlas Sci. Pharmacol., 1987, 1, 107. Jones, C. R., Molenaar, P. and Summers, R. J.,7. Mol. Cell Cardiol., 1989, 21, 519. Brodde, O.-E., in: Receptor pharmacology and function, M. Williams et al. (eds), Marcel Dekker, New York, 1989, 207. Michel, M. C., Brodde, O.-E. and Insel, P. A., Hypertension, 1990, 16, 107. Insel, P. A. and Wasserman, S. I., FASEBJ., 1990,4,2732. Bourne, H. R. et al.. Science, 1974, 184, 19. Kaumann, A. J. et al., Naunyn-Schmiedebergs Arch. Pharmacol., 1989, 339, 99. Lemoine, H., Ehle, B. and Kaumann, A. J., Naunyn-Schmiedebergs Arch. Pharmacol., 1985,331,40. McPherson, G. A. et al., Br. J. Pharmacol., 1984, 82, 897. Minneman, K. P., Hegstrand, L. and Molinoff, P. B., Mol. Pharmacol., 1979, 16, 21. Brodde, O.-E. etal., Circulation, 1990, 81, 914. Reithmann, C. et al., Eur. J. Pharmacol., 1989, 170, 243. Monopoli, A. et al.,J. Cardiovasc. Pharmacol., 1989, 14, 114. Gille, E. etal., Naunyn-Schmiedebergs Arch. Pharmacol., 1985, 331, 60. [20] Wellstein, A., Palm, D. and Belz, G. G., J. Cardiovasc. Pharmacol., 1986, 8 (Suppl. 11), S42. Lemoine, H., Schonell, H. and Kaumann, A. J., Br. J. Pharmacol., 1988, 95, 55. Wahlund, G. et al., Br. J. Pharmacol., 1990, 99, 592. Brodde, O.-E., J. Cardiovasc. Pharmacol., 1986, 8 (Suppl. 11), S29. Kaumann, A. J. and Lemoine, H., Naunyn-Schmiedebergs Arch. Pharmacol., 1985, 331, 27. Dooley, D. J., Bittiger, H. and Reymann, N. C., Eur. J. Pharmacol., 1986, 130, 137.

22

p-Adrenergic receptors

[Ch. 2

Table 1 — Selective drugs Compound

(—)-Isoproterenol (—)-Adrenaline ( —)-Noradrenaline (—)-Dopamine R0363 (±)-Dobutamine Xamoterol Terbutaline Procaterol Salbutamol Fenoterol (—j-Pindolol Celiprolol (—)-Propranolol (±)-Sotalol CGP 12,177 Atenolol Metoprolol Betaxolol Bisoprolol CGP 20/712A ICI 118,551

Intrinsic efficacy

Source

pK.Pi

pK, p2

+++ +++ +++ ++ ++ ++ + +++ ++ ++ ++ + + —

A A A A B C D A E A A A F A G A, H A A I

7.3 5.8 6.2 4.2 7.8 5.9 6.9 4.8 5.0 5.8 5.7 8.5 7.0 8.7 5.9 9.4 6.4 7.7 7.9 8.3 9.2 6.6

6.7 6.0 5.2 3.9 6.0 5.5 5.6 4.9 7.0 5.8 6.1 9.0 5.5 9.1 6.1 9.6 5.2 6.3 6.1 6.6 5.6 9.1

—

— — — — — —

J

H D

Ref.

12 13 13 12 14 15 5,16 15 16 15 15 5,17 5,17,18 5,19 15 17 20,21 22 14,20 20,23,24 25 13,20

The potency of p-adrenergic agonists can vary by 3-4 orders of magnitude among model systems and functional responses measured due to the enormous variability in post-receptor amplification mecha¬ nisms. Thus, this table gives affinities as determined from binding studies only. If classification of a certain functional response solely based on agonists is necessary, the order of potency of several such agonists should be used rather than their absolute potency. Based on the above affinities at p-adrenoceptor subtypes and other criteria, propanolol and CGP 12,177 are the non-selective antagonist of choice, with CGP 12,177 offering the additional advantage of great hydrophilicity; CGP 20,712A (in vitro) and bisoprolol (in vivo) are the prselective antagonists and ICI 118,551 is the p2-selective antagonist of choice because of their outstanding subtype selectivity. ICI 118,551 cannot be used in humans because of recent evidence that it may be carcinogenic.

23

3 Nicotinic receptors Ignaz Wessler Department of Pharmacology, University of Mainz, Obere Zahlbacher Str. 67, 6500 Mainz, Germany

SUBCLASSIFICATION The nicotine receptor (nAChR) is an allosteric protein shifting between multiple conformational states very rapidly. The nAChR consists of two to four different subunits (a, P, y, 5, e) and contains distinct functional domains (competitive agonist¬ binding sites, non-competitive ligand-binding sites, ion channel, immunogenic sites, phosphorylation sites). Although a complete cDNA sequencing of the subunits has been performed for some species (Torpedo californica, Torpedo marmorata, mouse, ox), the concept of subtypes of nAChR is only poorly developed. Cloning studies suggest at least five subtypes of nAChR, but a distinct classification of nAChR subtypes differing in their molecular, structural and pharmacological properties is, so far, not available. The only differentiation of nAChR subtypes which is widely accepted is the classic distinction between ganglionic (neuronal) and muscular nAChR. This concept, however, does not take into account the different molecular, electrophysiological and pharmacological properties of nAChR observed in differ¬ ent tissues. The following paragraphs briefly summarize evidence in favour of a heterogeneity of both muscular and neuronal nAChR. Muscular nAChR (electric organ and skeletal muscle) Both electric organ and muscular nAChR are composed of four different subunits (a, P, y, e or 6) and form the same quaternary structure (pentamer with four transmem¬ brane segments). Structural dissimilarities, however, have also been found, particu¬ larly in the competitive binding region of electric organ and skeletal muscle nAChR. Moreover, in skeletal muscles two different subtypes of nAChR containing different subunits are synthesized. The e-subunit, detected in calf, bovine and rat skeletal muscles, is supposed to replace the y-subunit during the formation of neuromuscular contact. Some evidence indicates that the y-containing nAChR corresponds to the extrasynaptically localized muscular nAChR.

24

Nicotinic receptors

[Ch. 3

Neuronal nAChR Neuronal nAChR differ from muscular nAChR with respect to their molecular, structural, electrophysiological and pharmacological properties, but some homolo¬ gies are also evidence (a-bungarotoxin binding sites in the brain and skeletal muscle). Neuronal nAChR appear to be composed of two different subunits (a2_4,p) only, but the exact subunit stoichiometry is unknown. Channel properties of neuronal nAChR differ from those of muscular nAChR (smaller conductance in neuronal than in muscular nAChR). At least three different subtypes of neuronal nAChR have been proposed on the basis of distinct molecular properties. The nAChR localized on cell bodies (soma of neurons in the central nervous system or ganglia in the peripheral nervous system) may be regarded as one subtype (function generally not blocked by a-bungarotoxin). A second type of neuronal nAChR is localized presynaptically, either in the peripheral nervous system at terminals of motoneurons (blockable by a-bungarotoxin) or in the central nervous system at terminals that release acetylcholine, dopamine, y-aminobutyric acid (GABA), noradrenaline or 5-hydroxytryptamine (5-HT). Evidence supporting the existence of these latter nAChR has been found in functional studies or in binding studies after respective lesion experiments. A further population of neuronal nAChR mediating depolarizaton is localized on non-myelinated nerve membranes (nodes of Ranvier, sensory nerve terminals, mammalian C-fibres, postganglionic sympathetic neurons). These nAChR, however, are pharmacologically less well characterized and probably do not represent a uniform population. For instance, it has been shown that depolarization of sympathetic neurons is blocked by hexamethonium (acting prefer¬ entially at neuronal nAChR), whereas depolarization of the pre-terminal part of motor nerves (last node of Ranvier) can be induced by decamethonium (acting preferentially at muscular nAChR). Neuronal nAChR differ also between different species (amphibians, avians, insects, mammals). Effects of agonists and antagonists at nAChR An approximate classification for agonists to mediate various biological events exists only for two actions: a preferential action at ganglia (carbachol, l,l-dimethyl-4phenylpiperazinium, lobeline, nicotine, tetramethylammonium) or at skeletal muscles (decamethonium, suxamethonium). The effects at ganglia appear to be more rapidly extinguished by desensitization than the effects at skeletal muscles. The antagonists hexamethonium, mecamylamine, neosurugatoxin, pentolinium and trimethapan are preferentially acting at ganglionic nAChR, whereas the non-depolar¬ izing muscle relaxants (alcuronium, atracurium, gallamine, pancuronium, pipecuronium, stercuronium, vecuronium) and benzoquinonium are preferentially acting at muscular nAChR. Vecuronium, however, has recently been shown to block catecho¬ lamine secretion from cultured adrenal medullary cells and neuromuscular trans¬ mission with a similar potency. Moreover, tubocurarine and dihydro-(3-erythroidine appear to have similar potencies at ganglionic and muscular nAChR. a-Neurotoxins (a-bungarotoxin, erabutoxin-b, siamensis toxin, etc.) are regarded to block exclusi¬ vely the muscular nAChR. a-Bungarotoxin, however, shows a specific binding at ganglia, the adrenal medulla and the brain, but this toxin blocks neither ganglionic transmission, nor catecholamine secretion, nor acetylcholine release from

Ch. 3]

Nicotinic receptors

25

autonomic neurons. Nevertheless, a-bungarotoxin (but not erabutoxin-b or siammensis toxin) has been shown to block some effects mediated by stimulation of neuronal nAChR (nicotinic autofacilitation of acetylcholine release from motoneur¬ ons, repetitive firing of motoneurons or of inhibitory interneurons in the rat cerebellum). K-Bungarotoxin, another a-toxin, has been reported to act as a specific antagonist at neuronal nAChR in the central and peripheral nervous system. The a-toxins bind-more or less-irreversibly to their binding sites.

LOCALIZATION The highest density of nAChR (a-bungarotoxin binding) is found in the electric organ of Torpedo californica or Torpedo marmorata (roughly 1000-fold higher than at skeletal muscles). Muscular nAChR are imbedded in the postsynaptic membrane of endplates of skeletal muscles, roughly 50 nm distant to the presynaptic membrane. Endplates are placed just in the middle of skeletal muscle fibres. Some few muscular nAChR are also present at the non-innervated part of the muscular membrane. Neuronal nAChR (peripheral nervous system) are localized at ganglia, adrenal medulla, motoneurons (terminal and axon) and non-myelinated nerve membranes. Neuronal nAChR (central nervous system) are localized at distinct areas within the brain and spinal cord. High-density binding of nicotine (rat) is found in the cerebral cortex (layers I and III/IV), substantia nigra, thalamus, superior colliculus and striatum, whereas low-level nicotine binding occurs in the hypothalamus, cerebellum and spinal cord. Nicotine binding in the spinal cord is mainly found in laminae II—III of the dorsal horn. Nicotine binding occurs also in the retina, optic nerve and optic tract. High-affinity binding for nicotine or acetylcholine shows only a small overlap (cerebral cortex (layer I) and superior colliculus) with a-bungarotoxin binding. High-density a-bungarotoxin binding occurs in the cerebral cortex (layer VI), hypothalamus, hippocampus and inferior colliculus. nAChR mediating hyper¬ polarization have also been found on cultured astrocytes.

SOURCES A. Commercially available. B. Research councils of national tobacco companies. C. Originally synthesized by R. Barlow, Department of Pharmacology, Medical School, University of Bristol, UK. D. Wellcome, 160 Euston Road, London, UK. E. Organon Teknika NV, Veedijk 58, 2300 Turnhout, Belgium. F. V. A. Chiappinelli, St Louis University Medical Center, Department of Pharmacology, 1402 S. Grand Blvd, St Louis, MO 63104, USA. G. Roche, Grenzacher Str. 124, Ch 4002 Basel, Switzerland.

REVIEW ARTICLES a. Oswald, R. E. and Freeman, J. A. 1981. Alpha-bungarotoxin binding and central nervous system nicotonic acetylcholine receptors. Neuroscience, 6, 1.

26

Nicotinic receptors

[Ch. 3

b. Conti-Tronconi, B. M. and Raftery, M. A. 1982. The nicotinic cholinergic receptor: correlation of molecular structure with functional properties. Ann. Rev. Biochem., 51, 491. a , c. Peper, K., Bradley, R. J. and Dreyer, F. 1982. The acetylcholine receptor at the neuromuscular junction. Physiol. Rev., 62, 1271. d. Dolly, J. O. and Barnard, E. A. 1984. Nicotinic acetylcholine receptors: an overview. Biochem. Pharmacol., 33, 841. i e. Popot, J. L. and Changeux, J.-P. 1984. Nicotinic receptor of acetylcholine: structure of an oligomeric integral membrane protein. Physiol. Rev., 64, 1162. f. Chiappinelli, V. A. 1985. Actions of snake venom toxins on neuronal nicotinic receptors and other neuronal receptors. Pharmacol. Ther., 31, 1. g. Wennogle, L. P. 1986. The end-plate acetylcholine receptors: structure and function, in: Kharkevich, D. A. (ed.), Handbook of experimental pharmacology, Vol. 79, Springer, Berlin, 17. h. Changeux, J.-P. and Revah, F. 1987. The acetylcholine receptor molecule: allosteric sites and the ion channel. Trends Neurosci., 10, 245. i. Clarke, P. B. S. 1987. Recent progress in identifying nicotinic cholinoreceptors in mammalian brain. Trends Pharmacol. Sci., 8, 32. j. Colquhoun, D., Ogden, C. D. and Mathie, A. 1987. Nicotinic acetylcholine receptors of nerve and muscle: functional aspects. Trends Pharmacol. Sci., 8, 465. k. Maelicke, A. 1988. Structure and function of the nicotinic acetylcholine receptor, in: Whittaker, V. P. (ed.), Handbook of experimental pharmacology, vol. 86, The cholinergic synapse. Springer Verlag, Berlin, p. 267. l. Deneris, E. S., Connolly, J., Rogers, S. W. and Duvoisin, R. 1991. Pharmacological and functional diversity of neuronal nicotine acetylcholine receptors. Trends Pharmacol Sci., 12, 34.

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Feldberg, W. and Fessard, A., J. Physiol. (Lond.), 1942, 101, 200. Gopfert, H. and Schafer, H., Pfliigers Arch. Ges. Physiol., 1938, 239, 597. Langley, J. N.,7. Physiol. (Lond.), 1905, 33, 374. Feldberg, W. and Gaddum, J. H.,7. Physiol. (Lond.), 1934, 81, 305. Wilson, S. P. and Kirshner, N.,7. Neurochem., 1977, 28, 687. Kopin, I. J. Ann. NY Acad. Sci., 1967, 144, 558. Loffelholz, K., in: Paton, D. M. (ed.), The release of catecholamines from adrenergic neurons, Pergamon Press, Oxford, 1978, p. 275. Dettbarn, W. D., Nature, 1960, 186, 891. Douglas, W. W. and Ritchie, J. M., J. Physiol. (Lond.), 1960, 150, 501. Ritchie, J. M., Ann. NY Acad. Sci., 1967, 144, 504. Krnjevic, K., in: Iversen, L. L., Iversen, S. D. and Snyder, S. H. (eds), Handbook of Psychopharmacology, vol. 6, Plenum, New York, 1975, p. 97. Caulfield, M. P. and Higgins, G. A., Neuropharmacology, 1983, 22, 347. De La Garza, R. et al., Neuroscience, 1987, 23, 887. Schworer, H. et al., Naunyn-Schmiedebergs Arch. Pharmacol., 1989, 336, 127. Wessler I., Trends Pharmacol. Sci., 1989, 10, 110. Beani, L. etal., Naunyn-Schmiedebergs Arch. Pharmacol., 1985, 331, 293. Valentimo, R. J. and Dingledine, R.,J. Neurosci., 1981, 1, 784. De Belleroche, J. S. and Bradford, H. F., Brain Res., 1978, 142, 53. Schwartz, R. D. et al.,J. Neurochem., 1984, 42, 1495. Reavill, C. et al., Neuropharmacology, 1988, 27, 235. Martino-Barrows, A. M. and Kellar, K. J., Mol. Pharmacol., 1987, 31, 169. Caulfield, M. P. and Higgins, G. A., Neuropharmacology, 1983, 22, 347. Wessler, I. et al., Naunyn-Schmiedebergs Arch Pharmacol., 1987, 335, R77. Paton, W. D. M. and Savini, E. C., Br. J. Pharmacol. Chemother., 1968, 32, 360.

Ch. 3] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49]

Nicotinic receptors

27

Barlow, R. B. and Franks, F., Br. J. Pharmacol., 1971, 42, 137. van Rossum, J. M., Int. J. Neuropharmacol., 1962, 1, 97. Trendelenburg, U., Ergebn. Physiol., 1967, 59, 1. Voile, R. L., Annu. Rev. Pharmacol., 1969, 9, 135. Blaber, L. C. and Goode, J. W., Int. J. Neuropharmacol., 1968, 7, 429. Kharkevich, D. A. and Fisenko, V. P., 1986, in: Kharkevich, D. A. (ed.) Handbook of experimental pharmacology., vol. 79, Springer, Berlin, p. 171. Colquhoun, D., in: Kharkevich, D. A. (ed.), Handbook of experimental pharmacology, vol. 79, Springer, Berlin, 1986, p. 59. Kharkevich, D. A. and Shorr, V. A., in: Kharkevich, D. A. (ed.) Handbook of experimental pharmacology, vol. 79, Springer, Berlin, 1986, p. 191. Bowman, W. C. and Webb, S. N.,7. Pharm. Pharmacol., 1972, 24, 762. Durant, N. N. et al., Eur. J. Pharmacol., 1977, 46, 297. Wessler, I. et al., Naunyn-Schmiedebergs Arch. Pharmacol., 1986, 334, 365. Hughes, R., in: Kharkevich, D. A. (ed.), Handbook of experimental pharmacology, vol. 79, Springer, Berlin, 1986, p. 529. Salt, P. et al., Br. J. Anaesth., 1980, 52, 313. Docherty, J. R. and McGrath, J. C., Br. J. Pharmacol., 1978, 64, 589. Conti-Tronconi, B. M. and Raftery, M. A., Annu. Rev. Biochem., 1982, 51, 491. Millington, W. R. et al.. Brain Res., 1985, 340, 269. Osswald, R. E. and Freeman, J. A., Neuroscience, 1981, 6, 1. Chiappinelli, V. A., Pharmacol. Ther., 1985, 31, 1. Marshall, L. M., Proc. Natl. Acad. Sci. USA., 1981,78, 1948. Freeman, J. A. et al.. Neuroscience, 1980, 5, 929. Wolf, K. M. et al.. Brain Res., 1988, 439, 249. van Rossum, J. M., Int. J. Neuropharmacol., 1962, 1, 403. Blackman, J. G., Proc. Univ. Otago Med. Sch., 1970, 48, 4. Large, W. A. and Sim, J. A., Br. J. Pharmacol., 1986, 89, 583. Eglen, R. M. et al., Br. J. Pharmacol., 1989, 98, 499.

28

[Ch. 3

Nicotinic receptors

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30

Nicotinic receptors

[Ch. 3

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5-Hydroxytryptamine receptors

[Ch. 5

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Table 1 (Continued)

The major features of 5-HT receptor subtypes

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