Ciba Foundation Symposium - Molecular Properties of Drug Receptors

309 Pages·1970·4.739 MB·English

MOLECULAR PROPERTIES
OF DRUG RECEPTORS
MOLECULAR PROPERTIES OF
DRUG RECEPTORS
A Ciba Foundation Symposium
Edited by
RUTH PORTER
and
MAEVE O’CONNOR
I.
& A. CHURCHILL
104 GLOUCESTER PLACE, LONDON
I 970
First published 1970
With9 1 illustrations
International Standard Book Number07000 14608
@ Longman Group Ltd, I970
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, photo-
copying, recording or otherwise, without the prior permission ofthe copyright owner.
Printed in Great Britain.
F. H. C. Crick Chairman’s opening remarks I
W. D. M. Paton Receptors as defined by their pharmacological
properties 3
Discussion Burgen, Changeux, Crick, Karlin, Mayer, Paton, Rang,
Silman, Spector, Wyman 30
S. Thesleff The cholinergic receptor in skeletal muscle 33
Discussion Burgen, Changeux, Crick, Paton, Rang, Silman, Singer,
Spector, Stryer, Theslef, Waser 39
S. E. Mayer Adenyl cyclase as a component of the adrenergic
receptor 43
Discussion Burgen, Changeux, Mayer, Singer, Waser 56
P. G. Water On receptors in the postsynaptic membrane of the
motor end plate 59
Discussion Ascher, Burgen, Changeux, Crick, jardetzky, Karlin,
Mayer, Paton. Silman, Singer, Theslef. Waser 69
General Discussion Ascher, Burgen, Changeux, Crick, jardetzky, Mayer,
Paton, Singer, Theslef, Waser 77
C. R. Beddell Crystallographic studies of the active site of lyso-
1. Moult zyme 85
D. C. Phillips
Discussion Burgen, Crick, jardetzky, Paton, Phillips, Rang.
Richards, Singer, Stryer, Waser, Wyman I03
0. Jardetzky Nuclear magnetic resonance studies of protein
binding sites: the complex of staphylococcal nuclease
with 3’.5’-thymidine diphosphate I I3
Discussion Crick, jardetzky, McConnell, Paton, Phillips, Richards,
Silman, Singer, Waser, Wyman I29
L. Stryer Fluorescent probes of biological macromolecules I33
Discussion Changeux, Crick. jardetzky, McConnell, Paton, Singer,
Stryer, Wyman I 50
General Discussion Brenner, Burgen, Changeux, Crick, jardetzky, Karlin,
Mayer. McConnell, Paton, Phillips, Rang, Richards,
Silman, Singer, Stryer I55
1. Wyman The interaction of the subunits of haemoglobin as a
mechanism of control I6 7
Discussion Brenner, Burgen, Changeux, Crick, Kirschner, McCon-
nell. Phillips. Singer, Spector, Stryer, Theslef,
Wyman I80
J. P. Changeux Conformational transitions in the course of mem-
R. Blumenthal brane excitation I97
M. Kasai
T. Podleskl
Discussion Brenner, Burgen, Changeux, Crick, Karlin, Paton,
Silman, Singer, Stryer 214
V
vi CONTENTS
General Discussion Burgen, Changeux, Crick. Mayer, McConnell, Richards,
Silman, Singer 219
S. J. Singer Afnnity labelling of protein activesites 229
Discussion Brenner, Crick, Mayer, Paton, Phillips, Rang, Richards,
Silman, Singer, Stryer, Theslef, Waser 242
A. Karlin Counting acetylcholine receptors in the electroplax 247
J. Prives
W. Deal
M. Winnik
Discussion Brenner, Burgen, Changeux, Crick, Karlin, Singer 259
A. S. V. Burgen The natureofcomplex formation 263
Discussion Brenner, Burgen, jardetzky, Phillips, Singer 268
Final Discussion Ascher, Brenner, Burgen. Changeux, Crick, jardetzky,
Karlin, Mayer, McConnell, Paton, Potter, Rang,
Richards, Silman, Singer. Theslef, Waser 27 I
Author index 29 I
Subject index 292
Membership
Symposium on Molecular Properties of Drug Receptors
held 27th-29th January 1970
F. H. C. Crick MRC Laboratory of Molecular Biology, University
(Chair man) Post raduate Medical School, Hills Road, Cambridge,
CBZIQH, England
P. Ascher Laboratoire de Neurophysiologie Cellulaire, Centre
d’kudes de Physiologie Nerveuse, 4 Avenue Gordon-
Bennett, Paris 16, France
S. Brenner MRC Laboratory of Molecular Biology, University Post-
graduate Medical School, Hills Road, Cambridge CB2
2QH, England
A. S. V. Burgen Dept of Pharmacology, University of Cambridge, Downing
Street, Cambridge CB2 3EF, England
J. P. Changeux lnstitut Pasteur, 25 rue du Docteur Roux, Paris 15, France
0. Jardetzky Dept of Pharmacology, Stanford University School of
Medicine, Stanford, California 94305. U.S.A.
A. Karlin Dept of Neurology, College of Physicians and Surgeons,
Columbia University, New York. N.Y. 10032, U.S.A.
K. Kinchner Dept of Biochemistry, Stanford University School of
Medicine, Stanford, California 94305, U.S.A.
H. M. McConnell Dept of Chemistry, Stanford University, Stanford,
California 94305, U.S.A.
S. E. Mayer Dept of Medicine, School of Medicine, University of
California, San Diego, La Jolla, California 92037, U.S.A.
W. D. M. Paton University Dept of Pharmacology, South Parks Road,
Oxford, England
D. C. Phillips Dept of Zoology. Laboratory of Molecular Biophysics,
Parks Road, Oxford, England
L. T. Potter Dept of Biophysics, University College London, Gower
Street, London, W.C. I, England
H. P. Rang University Dept of Pharmacology, South Parks Road,
Oxford, England
F. M. Richards Dept of Molecular Biophysics and Biochemistry, Yale
University, Box 1937, Yale Station, New Haven, Conn.
06520, USA.
1. Silman Dept of Biophysics, The Weizmann Institute of Science,
Rehovoth, Israel
S. J. Singer Dept of Biology, University of California, San Diego, La
Jolla, California 92037, U.S.A.
vii
viii MEMBERSHIP
R. G. Spector Dept of Pharmacology, Guy’s Hospital Medical School,
London, S.E. I, England
L. Stryer Dept of Molecular Biophysics and Biochemistry, Yale
University. Box 1937, Yale Station, New Haven, Conn.
06520. U.S.A.
S. Thesleff Dept of Pharmacology, University of Lund, Lund, Sweden
P. Waser Pharmakologisches lnstitut der Universitat Ztirich,
Gloriastrasse 32,8006 Zurich, Switzerland
J. Wyman lstituto Regina Elena, Viale Regina Elena 291,00161 Rome,
Italy
The Ciba Foundation
The Ciba Foundation was opened in 1949 to promote
international cooperation in medical and chemical re-
search. It owes its existence to the generosity of CIBA
Ltd, Bade, who, recognizing the obstacles to scientific
communication created by war, man’s natural secretiveness, dis-
ciplinary divisions, academic prejudices, distance, and differences
of language, decided to set up a philanthropic institution whose
aim would be to overcome such barriers. London was chosen
as its site for reasons dictated by the special advantages of English
charitable trust law (ensuring the independence of its actions),
as well as those of language and geography.
The Foundation’s house at 41 Portland Place, London, has
become well known to workers in many fields of science. Every
year the Foundation organizes six to ten three-day symposia and
three to four shorter study groups, all of which are published in
book form. Many other scientific meetings are held, organized
either by the Foundation or by other groups in need of a meeting
place. Accommodation is also provided for scientists visiting
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The Foundation’s many activities are controlled by a small
group of distinguished trustees. Within the general framework
of biological science, interpreted in its broadest sense, these activi-
ties are well summed up by the motto of the Ciba Foundation:
Consocient Gentes-let the peoples come together.
ix
MOLECULAR PROPERTIES OF DRUG RECEPTORS
RUTH PORTER & MAEVE O’CONNOR
Copyright 0 1970 Ciba Foundation
CHAIRMAN’S OPENING REMARKS
DRF . H. C. CRICK
THEp rogramme of our meeting has a logical structure, starting off with
the pharmacological properties of receptors, going on to the structure of
active sites in enzymes, then to conformational changes-that is really to
proteins and what they can do-and finally to the isolation and characteriza-
tion of receptors themselves. There is general agreement now, from what
we know of molecular biology as a whole, that receptors are likely to be
proteins, or at least that proteins are a very important part of receptors.
There have also been developments,e specially in the last five to seven years,
in our knowledge of protein structure. The basic idea of the symposium is
to try to bring these two aspects together. This is somewhat of an experi-
ment in that we still don’t know fully what proteins can’t do, though we
do know fairly well a number of things they can do and we have a shrewd
idea ofthe sort ofway they do them. But we still can’t predict, for example,
how they fold up. These are limitations in our knowledge which we hope
will be removed in the next five or ten years.
The other general remark I will make is that people here come from very
different disciplines. I would therefore appeal to people on both the
pharmacological side and the protein side not just to talk to the people who
already know the field but to the opposite side. My only usefulness as
Chairman is that I have got to the stage where I hardly know about either
side. Consequently up to a point I can ask the silly questions, but I hope that
everyone else will do so too ifa speaker is usingjargon about his own subject.
I
MOLECULAR PROPERTIES OF DRUG RECEPTORS
RUTH PORTER & MAEVE O’CONNOR
Copyright 0 1970 Ciba Foundation
RECEPTORS AS DEFINED BY THEIR
PHARMACOLOGICAL PROPERTIES
W. D. M. PATON
University Department ofPharnracology, Oxfrd
THEp harmacological knowledge which has led to, and to some extent
defined, the idea of the drug receptor can be arranged in three parts,
concerned with (a) structure-action relationships and chemical specificityo f
drugs, (b) sites of action and the selectivity in the body of responses to drugs,
and (c) the quantitative functional relationships demonstrablei n drug action.
STRUCTURE-ACTION RELATIONSHIPS AND CHEMICAL SPECIFICITY
It has long been known that particular chemical structures produce
particular actions. Just over IOO years ago Crum Brown and Fraser (1869)
showed that the quaternizing with methyl iodide of a series of amines (such
as morphine, atropine, strychnine, nicotine) removed their characteristic
actions and produced compounds with a single action-curare-like. Their
generalization, which by hindsight we can see as a pointer to the trans-
mitter function of acetylcholine at the neuromuscular junction, is still one
of the best; and it prompted their proposal of a programme of a “calculus
of finite variations” for defining the functional relation between chemical
constitution and physiological action. This programme, though it often
leads to a quagmire, has had its successes, including the recognition of
families of drugs built around and approaching in structure some natural
transmitter or hormone such as acetylcholine (Table I) or noradrenaline;
other groups, such as local anaesthetics, the opiates, phenothiazines, barbitu-
rates, thiazide diuretics, veratrine derivatives and cardiac glycosides, must
reflect properties of biochemical molecules or structures still unidentified.
These studies have, ofcourse, produced ad hoc rules, useful in the develop
ment of new drugs, but clearly limited: the pharmaceutical industry
produces only one clinically successful drug for every 2000-5000 investi-
gated, and despite many efforts there is a lack of good antagonists, for
example to histamine (on gastric secretion) or to gastrin, bradykinin or the
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