The Prostaglandins. Pharmacological and Therapeutic Advances

334 Pages·1972·4.879 MB·English

by  M. F. Cuthbert (Eds.)

THE PROSTAGLANDINS
Pharmacological
and Therapeutic Advances
Edited by
M.F.Cuthbert, MB., Ph.D.(London)
Department of Pharmacology and Therapeutics
London Hospital Medical College.
WILLIAM HEINEMANN MEDICAL BOOKS LTD
LONDON
First published 1973
© M. F. Cuthbert, 1972
ISBN 0 433 07000 5
Printed in Great Britain by
The Whitefriars Press Ltd., London and Tonbridge
Contributors
R. W. Butcher, Ph.D.
Department of Biochemistry, University of Massachusetts.
M. P. L. Caton, B.Sc, Ph.D.
Research Laboratories, May and Baker Ltd., Dagenham, Essex.
M. F. Cuthbert, M.B., Ph.D.
Department of Pharmacology and Therapeutics, London Hospital
Medical College, University of London.
K. Hillier, B.Sc, Ph.D.
Nuffield Department of Obstetrics and Gynaecology, University of
Oxford.
K. J. Hittelman, Ph.D.
Department of Biochemistry, University of Massachusetts.
S. M. M. Karim, B.Pharm., M.Sc, Ph.D.
Department of Pharmacology and Therapeutics, Makerere Univer-
sity Medical School, Kampala.
I. H. M. Main, B.Pharm., Ph.D.
Department of Pharmacology, School of Pharmacy, University of
London.
E. E. Muirhead, M.D.
Department of Pathology, University of Tennessee.
J. Nakano, M.D.
Departments of Pharmacology and Medicine, University of
Oklahoma.
Priscilla J. Piper, B.Pharm., Ph.D.
Department of Pharmacology, Institute of Basic Medical Sciences,
Royal College of Surgeons of England.
ν
Preface
During the past three years there has been a remarkable growth of
interest in the prostaglandins. There would appear to be two main
reasons for this. Firstly, methods of biosynthesis and more recently total
synthesis, have advanced sufficiently to enable adequate quantities of
pure material to be made available for both fundamental research and for
clinical investigation; secondly, the prostaglandins have been found to be
potent uterine stimulants and to be effective in the induction of labour
and therapeutic abortion.
The prostaglandins are very widely distributed in animal and human
tissues and they have powerful effects on almost every physiological
process which has been studied, as is evident from a brief examination of
their pharmacological properties. These findings have suggested that the
prostaglandins may regulate or be involved in many physiological
processes. A function as 'local hormones' has been suggested but there is
as yet little evidence to support this concept.
The possible therapeutic applications of the prostaglandins have not
yet been extensively explored. On the present evidence it seems likely
that they will have an established place in the induction of labour and
therapeutic abortion. It is quite possible that the induction of abortion
will prove to be practicable at any stage of pregnancy and the widespread
use of the prostaglandins for this purpose may well give rise to social and
ethical problems. There are also important implications in the control of
fertility. Other potential applications, such as the control of blood
pressure and the treatment of bronchial asthma and peptic ulceration,
are at a very exploratory stage.
Extensive research into the properties of the prostaglandins has
inevitably led to an overwhelming number of publications. Although
reviews and the proceedings of some symposia have been published, most
of the information on the prostaglandins is distributed in the specialist
journals. The justification and aim of this book is to provide the
interested medical and scientific reader with a concise account of the
more important theoretical developments and also to outline those areas
in which the prostaglandins are being introduced into clinical practice or
have potential clinical application.
ix
χ Preface
In chapters one to four the chemistry and classification, distribution
and metabolism, general pharmacology and mechanism of action are
considered. The second part of the book contains chapters on the
relationship of the prostaglandins to the reproductive, cardiovascular,
respiratory and gastro-intestinal systems with an emphasis on the human
pharmacology and potential therapeutic applications. In the latter
context, contributors have been encouraged to be speculative and
although some of their suggestions regarding the possible use of the
prostaglandins may in the future prove untenable it is likely that the
next few years will see important developments in the clinical
application of the prostaglandins.
September 1972 M.F.C.
Acknowledgements
I should like to take this opportunity to thank my wife, Mrs Margaret
Cuthbert, BA and Mrs Ann Shannon (British Medical Association House)
for valuable assistance in checking the manuscripts and references, and
also Mr Geoffrey Jones for compiling the index. I am also indebted to Mr
R. F. Ruddick, Photographic Department and Mrs Pat Hannaford,
Medical Artist, both of the London Hospital, for help with the
illustrations, and to Dr Raymond Greene and to Mr Owen R. Evans of
William Heinemann Medical Books Ltd, for their consistent interest and
encouragement.
September 1972 M. F. CUTHBERT
xi
CHAPTER I
Chemistry Structure
and Availability
M. P. L. Caton
1. NOMENCLATURE
Prostaglandins are a group of closely related carboxylic acids
containing a cyclopentane ring with two adjacent carbon side chains, one
of which bears the carboxyl group at the terminal position. Most of the
naturally occurring prostaglandins may be regarded as derivatives of the
parent structure prostanoic acid (Fig. 1), the carbon atoms being
numbered as shown. Individual members of the series are then
distinguished by the number, type and arrangement of oxygen functions
and double bonds which are built into this basic system.
Natural prostaglandins are divided into four groups and although these
may be named in accordance with their relationship to prostanoic acid,
they are more conveniently referred to by the letters E, F, A and Β (Fig.
l).f All four groups have in common a trans double bond at the 13,
14 position and a hydroxyl group at C .The Ε and F series, often
1 5
referred to as the primary prostaglandins, both possess an additional
hydroxyl at C and are distinguished from each other by the presence of
n
a carbonyl function at C in the Ε series and a C hydroxyl in the F
9 9
series. The A and Β series may be regarded as dehydration products of
the Ε compounds whereby loss of water has occurred with removal of
the Cu hydroxyl and formation of a double bond in the ring. This
dehydration is readily effected chemically and it is considered that some
of the A prostaglandins derived from natural sources are in reality
artifacts formed from the Ε prostaglandins during the isolation
procedure.
The A prostaglandins, in which this additional double bond is at
Cio, n> are the primary products of the dehydration but are relatively
unstable and readily rearrange under alkaline conditions to the Β
t Very recently two members of a fifth series have been isolated in small
quantities. These are isomers of the A and Β series, having the ring double bond at
C i2 and they have been designated by the letter C (Jones, 1972).
1}1
1
2 M. P. L. Caton
Fig. 1. Prostanoic acid and some naturally occurring prostaglandins.
prostaglandins where the ring double bond lies between the two side
chains, i.e. at C . Because A and Β prostaglandins are conveniently
8j 12
characterized by their ultra-violet spectra they were formally known
respectively as prostaglandins 217 and prostaglandin 278, the numbers
referring to their U.V. absorption maxima (πιμ).
Each of these four principal series are subdivided according to whether
one or two additional side chain double bonds are present. The total
number of such double bonds is referred to by a subscript numeral after
Chemistry Structure and Availability 3
the letter, thus prostaglandin E (PGE ) has only the C double
1 X 13> 14
bond, PGE has a further (eis) double bond at C and PGE a third
2 5 >6 3
(eis) double bond at C . These double bonds occur in the same
17 18
positions in all four groups, although PGA and PGB have not yet been
3 3
isolated. Members of the A and Β series are also known with an
additional hydroxyl group at C .
19
Prostaglandins possess several asymmetric centres which give rise to a
number of possible stereoisomeric forms. Most prostaglandins from
natural sources have the stereochemistry shown for the examples in
Fig. 1, where the side chains are trans to each other, i.e. they are
oriented on opposite sides of the ring. C and C hydroxyl groups are in
9 u
the α-configuration, i.e. on the same side of the ring as the carboxylic
acid side chain. The C hydroxyl is also designated a. but that at C has
1S 19
the opposite configuration. (For this purpose substituents attached
below the plane of the ring are indicated in the formulae with a dotted
line and those above with a continuous line). The absolute stereo-
chemistry was determined in 1966, before which some publications
showed the side chains in the opposite configuration (Nugteren, Van
Dorp, Bergström, Hamberg and Samuelsson, 1966; Hamberg, 1968).
Stereochemical variants of these natural forms arise in three different
ways, some examples of which are given for PGEj in Fig. 2. First, the
side chains may lie in the alternative i.e. eis relationship to one another;
these are termed 8-isoprostaglandins (e.g. 8-iso-PGEj) and may be
considered as based upon the parent isoprostanoic acid, analogous to
prostanoic acid. Secondly, one or more hydroxyl groups may have the β
configuration. Here the C and C β hydroxyls are sometimes referred
n 15
to by the term epi, alternatively the C hydroxyl group can also be
15
named after the Cahn-Ingold-Prelog Convention, i.e. S for the α and R
for the epi or β form. Thirdly, all prostaglandins are also capable of
existing in two optically active forms because of the asymmetry of the
Fig. 2. Some stereoisomers of prostaglandin E .
1
4 M. P. L. Caton
molecule. Natural prostaglandins are laevorotatory and their mirror
images, which are dextrorotatory and have the side chains transposed are
referred to as the ent forms. All these stereochemical variants may of
course be combined with each other and it is therefore possible to
envisage a very large number of different isomers.
It should be pointed out that the stereochemistry is understood and
reference to it is therefore omitted in the abbreviated forms (PGEj etc.)
used for the principal natural prostaglandins. However, with the F series
the term a or β (e.g. PGF PGF^) is always added to denote the
la
configuration of the C hydroxyl group. $ This is because the PGF^
9
compounds (Fig. 2), although not occurring naturally, have long been
known together with the F compounds as reduction products of the Ε
a
prostaglandins and it has become established practice to distinguish them
in this way.
When it is desired to describe prostaglandins in terms of their full
systematic nomenclature, a method based on the structure of prostanoic
acid is adopted, details of which are given by Nugteren et al. (1966).
Thus the full systematic name of PGE is (-)-lla, 15(S)-dihydroxy-
X
9-oxo-l3-irarcs-prostenoic acid, where the (—) sign refers to the
laevorotation and the 'trans' to the C double bond.
13>14
A number of derivatives and structural variants of these natural
prostaglandins occur as metabolites and other types have been prepared
by biosynthesis and chemical synthetic methods. These have been
conveniently named after the natural group to which they are most
closely related or they may be described in terms of their relationship to
prostanoic acid. Prostaglandins where the side chains are one or more
methylene units shorter than normal are described by the terms nor,
dinor, trinor etc. and the corresponding longer chain compounds are
referred to as homo (Fig. 3). The letters α or ω are used here to signify
whether the terms apply to the carboxyhexyl i.e. a, or the hydroxyoctyl
Fig. 3. Prostaglandin Ε γ —side chain variants.