Ergot Alkaloids and Related Compounds

1015 Pages·1978·19.865 MB·English

by  B. Berde, E. Stürmer (auth.), B. Berde, H. O. Schild (eds.)

Handbuch der experimentellen
Pharmakologie
Vol. 49
Heffter-Heubner New Series
Handbook of Experimental
Pharmacology
Herausgeber Editorial Board
G. V. R. Born, Cambridge' O. Eichler, Heidelberg
A. Farah, Rensselaer, NY . H. Herken, Berlin
A. D. Welch, Memphis, TN
Beirat Advisory Board
E. J. Ariens . Z. M. Bacq . P. Calabresi . S. Ebashi . E. G. Erdos
V Erspamer . U. S. von Euler' W. S. Feldberg· G. B. Koelle' O. Krayer
T. A. Loomis' H. Raskova . M. Rocha e Silva' F. Sakai' J. R. Vane
P. G. Waser . W. Wilbrandt
Ergot Alkaloids and
Related Compounds
Contributors
W. H. Aellig . B. Berde . Th. Bucher· D. Chu . B.J. Clark
E. B. van Deusen . H. Eckert· A. Fanchamps . E. Fllickiger
J. Grauwiler . R. W Griffith· D. Hauser· Ch. Hodel
J. R. Kiechel . K. H. Leist· D. M. Loew . B. Matter
W Meier-Ruge . E. Mtiller-Schweinitzer . T. J. Petcher
E. del Pozo . B. P. Richardson· J. Rosenthaler . J. Rutschmann
K. Saameli . R. Salzmann· H. O. Schild· R. Schmidt
E. Schreier· P. A. Stadler· E. StUrmer· R. D. Venn· H. Wagner
H. P. Weber· H. Weidmann
Editors
B. Berde and H.O. Schild
Springer-Verlag Berlin Heidelberg New York 1978
B. BERDE, Forschung und Entwicklung, Pharmazeutisches Departement,
Sandoz AG, 4002 Basel, Schweiz
H. O. SCHILD, Emeritus Professor of Pharmacology in the University of London,
University College London, London WCI, Great Britain
With 159 Figures
ISBN-13: 978-3-642-66777-0 e-ISBN-13: 978-3-642-66775-6
001: 10.1007/978-3-642-66775-6
Library of Congress Cataloging in Publication Data. Main entry under title: Ergot alkaloids and related compounds. (Handbook
of experimental pharmacology: New series; v. 49) Bibliography: p. . Includes index. I. Ergot. 2. Alkaloids. I. Aellig. W.H. II. Berde.
Botond. 1919- . III. Schild. Heinz Otto. IV. Series: Handbuch der experimentellen Pharmakologie: New series; v. 49. QP905.H3
vol. 49 [RM666.E8]615'.1'08s [615'.7]77-14126
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Preface
Une decouverte scientifique ... n'est ja
mais l'reuvre d'un seul homme et chacun
de ceux qui y ont concouru lui ont donne
bien des veilles.
Louis Pasteur
Traditionally every volume of the Handbook of Experimental Pharmacology is
expected to give a comprehensive account of the topic it is devoted to. This
is a relatively easy task if the subject has a short history, but if the problems
in question have been worked on for half a century or longer the feasibility of
integral coverage becomes questionable. In such cases more attention is usually
given to the literature of the last decades, whereas older findings are dealt with
in a summary fashion - with due exception to findings which can be considered
classic. The situation is particularly complex if the origin of the subject is a natural
drug whose actions - proven or alleged - were first recorded several centuries ago
and where medical use can be traced back at least one and a half centuries (STEARNS,
1808) - as is the case of ergot of rye.
As editors of the present volume of this Handbook, we did not have to face
the full impact of these difficulties as two previous volumes have already been
devoted to the pharmacologic actions of substances extracted from ergot of rye.
The first of these, written by Arthur Cushny in 1914, was published in 1924
[A.R. CUSHNY: Mutterkorn. Handb. exper. Pharmakol. II, 2, 1297-1354 (1924)].
The second, by George Barger, appeared in 1938 [G. BARGER: The Alkaloids
of Ergot. Handb. exper. Pharmakol. (Erg.-Werk) VI, 84-226 (1938)]. Nevertheless,
the present volume had to bridge a gap of nearly four decades during which
time tremendous developments have taken place in this field. Besides reviewing
this progress, we have attempted a synopsis of the whole field in which recent
work is of course treated preferentially, but without neglecting the older literature
whenever this was necessary for the understanding of the present state of knowledge.
Only data obtained with chemically defined compounds, namely chemical entities
containing the tetracyclic ergolene- or ergoline-ring system, were considered.
A history of ergot with its colorful medieval aspects - mainly the history of
ergot intoxication due to the agricultural standards of the time - has been excluded
from this volume. This subject is dealt with in considerable detail in a number
of treatises such as DE JUSSIEU et aI., 1779 ; FALCK, 1855; KOBERT, 1889; HUSEMANN,
1903; BARGER, 1931; STOLL, 1943; GUGGISBERG, 1954; HOFMANN, 1964; LEDERER,
1961; BOVE, 1970; BAUER, 1973, and there is not much to be added to the story.
An important question was, of course, where the limits of "pharmacology"
were to be drawn in this volume. That human pharmacology or clinical pharmacol
ogy had to be included seemed self-evident, the aim of the development of agents
with therapeutic usefulness being ultimately directed for usage in man. Admittedly,
it is not always easy to draw the line between clinical pharmacology and therapeu
tics, the latter being outside the scope of this volume. We aimed at a rather
VI Preface
restrictive definition of clinical pharmacology, and pharmacologic findings in man
were in principle incorporated in individual chapters in relation to specific groups
of problems such as circulation and nervous system. Only in two instances (Chapters
VII and VIII) have chapters exclusively devoted to human pharmacologic aspects
been included, due to the complexity of the topics in question.
According to tradition, but also of necessity, a chapter dealing with chemical
aspects (Chapter II) is included. Its aim is to give an overview of the complex
chemistry of ergot alkaloids. It is deliberately entitled "chemical background,"
but is addressed particularly to pharmacologists, biologists, and doctors, rather
than to chemists.
Pharmacokinetics and data concerning drug metabolism are dealt with in a
separate chapter (Chapter XI). This aspect is of evident importance although as
in most other well-studied fields of pharmacology, much more is known of what
the compounds do to the living body than what the living body does to the
active compounds.
We believe that the description of a group of biologically active substances
is incomplete without their toxicologic characterization. The chapter in question
(Chapter XII), however, makes no attempt at completeness. It should rather serve
to give the reader some degree of general orientation.
The bulk of the book is devoted to traditional pharmacology. It includes an
introductory section placing the therapeutically important ergot alkaloids in per
spective (Chapter 1) and a series of main sections dealing with fundamental receptor
considerations (Chapter III) and various body systems on which ergot alkaloids
exert their effects.
The Subject Index was prepared by Dr. U. BRUCKNER. We wish to thank him for
making this important contribution. Our gratitude is also expressed to Mr. E.
ERFLING for compiling the Author Index.
Basel and London, May 1977
B. BERDE and H.O. SCHILD
References
Barger, G.: Ergot and Ergotism. Edinburgh: Gurney & Jackson 1931
Barger, G.: The alkaloids of ergot. Handb. exper. Pharmakol. (Erg.-Werk) 6,84-226 (1938)
Bauer, V.H.: Das Antonius-Feuer in Kunst und Medizin. In: Sitzungsberichte der Heidelberger
Akademie der Wissenschaften. Mathematisch-Naturwissenschaftliche Klasse. Suppl. Jahr
gang 1973. Berlin-Heidelberg-New York: Springer 1973
Bove, F.J.: The Story of Ergot. Basel-New York: Karger 1970
Cushny, A.R.: Mutterkorn. Handb. exper. Pharmakol. 11/2, 1297-1354 (1924)
De Jussieu, A.-L., Paulet, Saillant, Tessier, H.A.: Recherches sur Ie feu Saint-Antoine. Histoire
de la Societe Royale de Medicine. Annee 1776, pp. 260-302. Paris: Pierres 1779
Hofmann, A.: Die Mutterkorn-Alkaloide. Stuttgart: Enke 1964
Falck, C.Ph.: Vergiftungen durch Mutterkorn. In: Handb. der speziellen Pathologie und Thera
pie, Vol. II, Part I, pp. 311-327. Erlangen: Enke 1855
Guggisberg, H.: Mutterkorn. Vom Gift zum Heilstoff. Basel-New York: Karger 1954
Husemann, T.: Ergotismus. In: Handb. der Geschichte der Medizin. Neuburger, M., Pagel,
J. (eds.), Vol. II, pp. 916-926. Jena: G. Fischer 1903
Preface VII
Kobert, R.: Zur Geschichte des M utterkorns. In: Historische Studien aus dem Pharmakologi
schen Institute der Kaiserlichen Universitiit Dorpat, Vo!. I, pp. 1-47. Halle a.S.: von
Tausch & Grosse 1889
Lederer, J.: Les mendiants de Bruegel, un document pour I'histoire des Flandres sous I'occupa
tion espagnole. Scrinium Lovaniense Melanges historiques Etienne van Cauwenbergh. Lou
vain 1961, pp. 452-465 (Univ. de Louvain, Recueil de travaux d'histoire et de philo!.
4e serie, fasc. 24)
Stearns, J.: Account of the pulvis parturiens, a remedy for quickening child-birth. Med.
Repository N.Y. 5, 308 (1808)
Stoll, A.: Altes und Neues tiber Mutterkorn. Mitteilungen der Naturforschenden Gesellschaft
Bern aus dem Jahre 1942, pp. 45-80. Bern: P. Haupt 1943
Contents
CHAPTER I
Introduction to the Pharmacology of Ergot Alkaloids and Related Compounds as
a Basis of Their Therapeutic Application.
B. BERDE and E. STURMER. With 16 Figures. . . . . . . . ..
CHAPTER II
Chemical Background. J. RUTSCHMANN and P.A. STADLER. With 32 Figures
A. Occurrence, Biosynthesis, and Production . . . . . 29
I. Presence of Ergot Alkaloids in the Plant Kingdom 29
2. Biogenesis. . . . . . . . . . . . . . . . 29
3. Production . . . . . . . . . . . . . . . 31
B. Structure and Synthesis of the Natural Alkaloids 32
I. General Structural Aspects 32
2. Structure of Ergot Alkaloids. . . . . . . . 34
3. Synthesis of Ergot Alkaloids. . . . . . . . 37
C. Chemical Modifications in the Lysergic Acid Half of Ergot Alkaloids 38
I. Substitutions in Position I. . . . . . . . . . 38
2. Substitutions in Position 2. . . . . . . . . . . . . . . . 40
3. Chemical Transformations in Positions 4 and 5. . . . . . . 43
4. Replacement of the N-Methyl Group in Position 6 by Other
Substituents . . . . . . . . . . . . . . . . . . . . . . 45
5. Reactions Involving Position 7. . . . . . . . . . . . . . 46
6. Modifications of the Carboxylic Acid Function of d-Lysergic Acid 46
7. Reactions at Position 8 . . . . . . . . . . . . . . . . . 53
8. Derivatives of 6-Methyl-8-ergolene-8-carboxylic Acid . . . . 55
9. Chemical Transformations on the Double Bond in Position 9, 10. 57
10. Substitution Reactions in the Benzene Ring . . . . . . 60
D. Chemical Modification in the Peptide Part of Ergot Alkaloids 61
I. The Aci-Rearrangement. . . . . . . . . . . . . . . 61
2. Synthesis of Analoga of Natural Ergot Peptide Alkaloids 62
3. Substitution of L-Proline by Other Amino Acids in Ergot Peptide
Alkaloids . . . . . . . . . . . . . . . . . . . . . . . 64
4. Synthetic Ergot Peptide Alkaloids Modified in Position 5' . . 64
E. Some Analytical Tools for the Determination of Ergot Alkaloids 67
1. Separation of Ergot Alkaloids . . . . . . . . . . . . . . 67
x
Contents
2. Assay of Ergot Alkaloids 68
F. Subject Index. 69
G. References. . . . . . . . 78
CHAPTER III
Basic Pharmacological Properties. E. MOLLER-SCHWEINITZER and H. WEIDMANN.
With Contributions by R. SALZMANN, D. HAUSER, H.P. WEBER, T.J. PETCHER,
and TH. BUCHER. With 42 Figures
A. Introduction . . . . . . . . . . . . 87
Competitive Drug Antagonism . . . . 88
Corollaries of Competitive Antagonism 90
Affinity and Intrinsic Activity (Efficacy) 90
Receptor Classification . . . . . . . 91
Noncompetitive Antagonism . . . . . 93
B. Actions of Ergot Alkaloids at 5-HT Receptors 94
I. Actions of Ergot Alkaloids at Extraneuronal 5-HT Receptors 94
2. Effects of Ergot Alkaloids on 5-HT Metabolism . . . . . . 112
3. Effects of Ergot Alkaloids on Neuronal 5-HT Receptors. . . 120
4. Effects of Ergot Alkaloids on 5-HT- Sensitive Enzyme Systems 131
C. Actions of Ergot Alkaloids at Dopamine Receptors . . . . . . 133
I. Actions of Ergot Alkaloids at Extraneuronal Dopamine Receptors 133
2. Interaction of Ergot Alkaloids With Indirect Dopamine Effects.. 134
3. Actions of Ergot Alkaloids at Neuronal Dopamine Receptors .. 134
4. Effects of Ergot Alkaloids on Dopamine-Sensitive Enzyme Systems. 138
5. Effects of Ergot Alkaloids on Dopamine Receptors Mediating Hormone
Secretion . . . . . . . . . . . . . . . . . . . . . . . 139
D. Actions of Ergot Alkaloids at Adrenoceptors. R. SALZMANN and
TH. BUCHER . . . . . . . . . . . . . . . . . . . . . . . 140
I. Effects of Ergot Alkaloids Mediated by Peripheral tx-Adrenoceptors . 140
2. Depletion of Noradrenaline From Tissues by Ergot Alkaloids .. 159
3. Effects of Ergot Alkaloids on Noradrenaline Release and Theories
on the Mechanism of Noradrenaline" Overflow". . . . . . .. 161
4. Effects of Ergot Alkaloids on the Responses of Organs to Stimulation
of Their Sympathetic Innervation. . . . . . . . . . . . . . .. 170
5. Actions of Ergot Alkaloids at fJ-Adrenoceptors. . . . . . . . .. 177
E. The Shape of Ergotamine and Dihydroergotamine in Relation to Their
Interaction With tx-Adrenoceptors. H.P. WEBER and T.J. PETCHER 177
F. Actions of Ergot Alkaloids at Acetylcholine Receptors. 182
G. Actions of Ergot Alkaloids at Histamine Receptors . . . . . . 182
H. Interaction of Ergot Alkaloids With Prostaglandins ..... 182
1. Interference of Ergot Alkaloids With Endogenous Prostaglandin
Synthesis . . . . . . . . . . . . . . . . . . . . . . . 182
2. Interference of Ergot Alkaloids With Prostaglandin Effects 184
J. Stimulation of Smooth Muscle by Ergot Alkaloids Mediated by
Miscellaneous Mechanisms. . . . . . . . . . . . . . . . . 185
Contents XI
1. Enhancement of Responses to Biogenic Amines by Ergot Alkaloids
in Vascular Smooth Muscles. . . . . . . . . . . . . . . .. 186
2. Enhancement of Responses to Biogenic Agents by Ergot Alkaloids
in Nonvascular Smooth Muscles . . . . . . . . . . . . 188
K. Biochemical Identification of Specific Binding Sites for Ergot
Alkaloids. D. HAUSER. . . . . . . . . . . . . . . . . . 191
1. Interaction of Ergot Compounds With Specific Sites in the
Central Nervous System. . . . . . . . . . . 192
2. Peripheral Binding Sites for Ergot Compounds. 196
L. References. . . . . . . . . . . . . . . . . . 196
CHAPTER IV
Effects on the Uterus. K. SAAMELI. With 16 Figures
A. Introduction . . . . . . . . . . 233
B. Actions on Uterine Motor Activity . 234
1. Peptide Alkaloids. . . . . . . . 235
2. Dihydrogenated Peptide Alkaloids 252
3. Lysergic Acid-Amides . 273
C. References. . . . . . . . . . . . 314
CHAPTER V
Actions on the Heart and Circulation. B.1. CLARK, D. CHU, and W.H. AELLIG.
With 15 Figures
A. Actions on Systemic Blood Pressure. . . . . . . 321
1. Nature of the Effect . . . . . . . . . . . . 321
2. Effects on Blood Pressure Control Mechanisms. 325
3. Effects on the Carotid Sinus and Impulse Transmission in
Sino-Aortic Nerves. . . . . . . . . . . . . . . . . 334
4. Effects on Responses to Catecholamines and 5-Hydroxytryptamine 335
5. Mechanisms Involved in the Hypotensive Action 339
6. Mechanisms Involved in the Pressor Action 345
B. Hemodynamic Effects . . . . . . 348
C. Effects on Regional Hemodynamics 352
1. Effects on Limb Blood Vessels . 352
2. Effects on Cranial Blood Vessels 363
3. Effects on Renal Blood Vessels. 366
4. Effects on Mesenteric Blood Vessels 368
5. Effects on Coronary Blood Vessels 369
6. Effects on Uterine Blood Vessels 370
D. Actions on the Heart . 371
1. Effects in Mammals 371
2. Effects in Amphibia 382
3. Effects in Molluscs . 385
E. Pharmacologic Basis for the Clinical Use of Ergot Alkaloids 387
1. Orthostatic Hypotension . . . . . . . . . . . . . . 387
XII Contents
2. Venous Thrombosis. 389
3. Shock. 390
4. Migraine 390
F. References . 399
CHAPTER VI
Effects on the Central Nervous System. D.M. LOEW, E.B. VAN DEUSEN, and W.
MEIER-RuGE. With 8 Figures
A. Introduction . . . . . . . . . 421
B. Early Evidence of Central Effects 422
I. Convulsive Ergotism in Man. 422
2. Early Description of Central Effects in Animals 423
3. The Question of" Toxic" versus" Therapeutic" Dose. 426
C. Whole-Animal Studies. . 426
I. Behavioral Excitation. . . . . . . . . . . 427
2. Behavioral Depression . . . . . . . . . . 428
3. Interaction With Centrally Depressant Drugs 430
4. Anticonvulsant Effects 435
5. Electroencephalogram. 439
6. Cerebral Blood Flow 448
7. Body Temperature . . 453
8. Emesis ...... . 457
D. Synaptic Transmission: Catecholaminergic Mechanisms 461
I. Criteria of Catecholaminergic Stimulation and Antagonism
at the Synaptic Level . . . . . . . 461
2. Agroclavine-Type Ergot Derivatives. . 469
3. Ergometrine . . . . . . . . . . . . 472
4. D-LSD, 2-Br-LSD, and Methysergide . 475
5. PRT 17-402 . 478
6. Ergocornine . . . . . . . . 479
7. Bromocriptine . . . . . . . 479
8. Other Ergopeptine Derivatives 484
9. Efficacy of Ergot Derivatives as Antiparkinsonian Agents 484
E. Synaptic Transmission: Serotoninergic Mechanisms . . . . 489
I. Criteria of Serotoninergic Stimulation and Antagonism at the
Synaptic Level 489
2. D-LSD ... 491
3. 2-Br-LSD .. 495
4. Methysergide 495
5. Other Lysergic Acid Derivatives 497
6. Ergopeptine Derivatives. . . . 498
F. Brain Metabolism. . . . . . . . 500
I. Brain Cyclic Adenosine Monophosphate. 500
2. Adenosine Triphosphate Metabolism in the Brain. 503