Medical History, 2004, 48: 153±174

``Receptive Substances'': John Newport Langley

(1852±1925) and his Path to a Receptor Theory
of Drug Action
ANDREAS-HOLGER MAEHLE*

Introduction
The concept of specific receptors that bind drugs or transmitter substances onto the cell,
thereby either initiating biological effects or inhibiting cellular functions, is today a corner-
stone of pharmacological research and pharmaceutical development. Yet, while the basic
ideas of this concept were first explicitly formulated in 1905 by the Cambridge physiologist
John Newport Langley (1852±1925), drug receptors remained hypothetical entities at least
until the end of the 1960s. Without doubt, the development of receptor-subtype specific
pharmaceuticalsÐespecially the beta-adrenergic receptor antagonist propranolol (intro-
duced in 1965)Ðpromoted the acceptance of the receptor concept in pharmacology. It was
only in the 1970s, however, that receptors began to be isolated as specific proteins of the
cell membrane and that their composition and conformation began to be explored. During
the last twenty years the modern techniques of molecular biology have helped to determine
the genetic basis of receptor proteins, to identify their amino acid sequences, and to further
elucidate their remarkable structural diversity as well as their similarities and evolutionary
relationships. Numerous receptor types and subtypes have since been characterized.1
Unsurprisingly therefore, the origins of the receptor theory have attracted the
interest of historians of medicine and science. In particular, John Parascandola has
traced the beginnings of the receptor idea in the work of Paul Ehrlich (1854±1915) and
J N Langley.2 More recently, the roots of the receptor concept in Ehrlich's immunological
research, i.e. his famous ``side chain theory'', have been examined in great detail by
* Prof. Dr. med. Andreas-Holger Maehle, PhD, 1983±86, vol. 2, pp. 37±72; P G Waser, `The
Centre for the History of Medicine and Disease, cholinergic receptor', ibid., vol. 3, pp. 157±202;
Wolfson Research Institute, University of Durham, S E Cozzens, Social control and multiple discovery
Queen's Campus, University Boulevard, Stockton-on- in science: the opiate receptor case, Albany, State
Tees TS17 6BH, United Kingdom. University of New York Press, 1989; J D Robinson,
Mechanisms of synaptic transmission: bridging the
I would like to thank the Wellcome Trust for its gaps (1890±1990), Oxford University Press, 2001,
support of this research through a Project Grant on the pp. 143±70, 199±218. On the history of research into
history of the drug receptor concept. Many thanks, for neurotransmission, see also J-C Dupont, Histoire
their helpful comments, are due to my colleagues in de la neurotransmission, Paris, Presses
the project, Prof. Robert F Halliwell and PD Universitaires de France, 1999.
Dr Cay-R udiger Prull, the latter also for his most 2
J Parascandola and R Jasensky, `Origins of
efficient assistance in accessing the primary sources. the receptor theory of drug action', Bull. Hist. Med.,
I would also like to thank the anonymous referees of 1974, 48: 199±220; J Parascandola, `The
this paper for their constructive suggestions. development of receptor theory', in Parnham and
Bruinvels, op. cit., note 1 above, vol. 3, pp. 129±56.
1
R G Shanks, `The discovery of beta adrenoceptor See also A-H Maehle, C-R Prull and R F Halliwell,
blocking drugs', in M J Parnham and J Bruinvels (eds), `The emergence of the drug receptor theory',
Discoveries in pharmacology, Amsterdam, Elsevier, Nature Reviews Drug Discovery, 2002, 1: 637± 41.

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 Andreas-Holger Maehle
Arthur M Silverstein.3 Ehrlich's work on receptors has also been related to the complex
circumstances of his academic career in a recent article by Cay-Rudiger Prull.4 By contrast,
we are only roughly oriented about Langley's path to the receptor concept.5 In fact, besides
Gerald Geison's discussion of Langley as a member of Michael Foster's Cambridge School
of Physiology,6 historians have generally neglected the extensive research of this, in
his own day, eminent scientist.
This paper intends to redress that historiographical imbalance and thus to enhance our
historical understanding of the origins of the drug receptor theory and of one of its founders.
After a brief account of Langley's life, this paper gives a detailed analysis of how he
developed, over a period of thirty years and in diverse research contexts, his ideas on
the mode of action of drugs, culminating in 1905 with the first full formulation of his
concept of ``receptive substances''. In particular, the influence of other British and of
Continental scientists on Langley's thought and experimentation will be considered.
This essay will illustrate how his ideas on drug receptors emerged from several different
issues that were then debated in physiology, and how they depended on specific physio-
logical research methods of the time. It will also show how Langley defended his concept
against his scientific critics and how he refined and elaborated upon the receptor idea during
this process. It will finally highlight how Langley used references to Ehrlich's earlier side
chain theory to consolidate his own concept of receptive substances, but simultaneously
asserted his intellectual independence from the German Nobel Prize winner. While Ehrlich
was in fact the first who developed, in the context of immunology, a receptor concept as
such, Langley first proposed a receptor theory of drug action. This drug receptor theory, in
turn, was later utilized in Ehrlich's chemotherapy. Langley's path to the receptor idea, as
this paper will make clear, was independent from that of Ehrlich and deeply embedded in the
physiological research of his time.

J N Langley: A Cambridge Man from Start to Finish

Born at Newbury on 10 November 1852, the son of a private schoolmaster, Langley was
first educated at home and then at Exeter Grammar School before he entered St John's
College, Cambridge, in October 1871.7 With the aim of qualifying for a career in the Civil
Service, he initially studied mathematics, history and other literary subjects, but changed his
3 7
A M Silverstein, Paul Ehrlich's receptor The biographical details of this section have
immunology: the magnificent obsession, San Diego, been taken from: `Langley, John Newport', entry
Academic Press, 2002. no. 3949 in Register, St John's College, Cambridge;
4
C-R Pr
ull, `Part of a scientific master plan? W M Fletcher, `John Newport Langley: in memoriam',
Paul Ehrlich and the origins of his receptor concept', J. Physiol., 1926, 61: 1±27; idem, `John Newport
Med. Hist., 2003, 47: 332±56. LangleyÐ1852±1925', Proc. R. Soc. Lond.,
5
See Parascandola and Jasensky, op. cit., series B, 1927, 101: xxxiii±xli; R du Bois-Reymond,
note 2 above, pp. 200±1, 211±6; M R Bennett, `The `John Newport Langley zum Gedachtnis',
concept of transmitter receptors: 100 years on', Ergebisse der Physiologie, 1926, 25: xv±xix;
Neuropharmacology, 2000, 39: 523±46. C S Sherrington, `Langley, John Newport', in
6
G L Geison, Michael Foster and the Cambridge J R H Weaver (ed.), Dictionary of National Biography
School of Physiology: the scientific enterprise in 1922±1930, Oxford University Press, 1937,
late Victorian society, Princeton University Press, pp. 478±81; G L Geison, `Langley, John Newport',
1978, pp. 236±44, 313±27. Langley is mentioned in in C C Gillispie (ed.), Dictionary of Scientific
passing in M Weatherall, Gentlemen, scientists and Biography, New York, Charles Scribner's Sons,
doctors: medicine at Cambridge, 1800±1940, 1973, vol. 8, pp. 14 ±19.
Woodbridge, Boydell Press, 2000.

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 John Newport Langley and a Receptor Theory of Drug Action
plans in his second year and began to read natural sciences. Langley was especially attracted
by the classes in elementary biology, embryology and physiology, which were held by
(later Sir) Michael Foster (1836±1907), then a Fellow, and Praelector of Physiology, at
Trinity College. Even before Langley graduated BA in 1875, Foster involved him in his
research. Langley's first study was concerned with the physiological effects of the drug
jaborandi (containing pilocarpine), which he examined in the frog, dog, rat and rabbit,
noting in particular its decelerating effect on the heart rate and a similarity of its action with
that of the alkaloid physostigmine.8 In the same year, 1875, Foster made him his
Demonstrator, in succession to Henry Newell Martin (1848±1896), who had left Cambridge
for a professorship at Johns Hopkins University in Baltimore.
In 1877 Langley was elected to a Fellowship at Trinity College, and in the subsequent
year he received his MA. By this time he had become interested in the effect of pilocarpine
on salivary secretion, which he studied in the dog and cat.9 Animal experimentation had
been legally regulated for the first time in Britain in 1876. The Cruelty to Animals Act of this
year required among other things that animals, especially dogs and cats, be anaesthetized
during experiments (unless insensibility defeated the object of the investigation).10 This
legal requirement was also reflected in Langley's published descriptions of his animal
experiments. While he had before mentioned his use of anaesthetics only in passing, he now
stated this fact prominently and explicitly.11
Some of his research on salivary secretion was carried out in the laboratory of the
Heidelberg physiologist Wilhelm K uhne (1837±1900), where Langley worked for several
months during 1877. The physiology of glandular secretion developed into Langley's first
major research field, in which he worked until about 1890, combining morphological,
physiological, and chemical methods of investigation.12 This area of interest was supple-
mented by anatomical and histological studies into the then debated problem of cerebral
localization and into neurodegeneration.13
8
J N Langley, `Preliminary notice of experiments various, most frequently morphia or chloroform,
on the physiological action of jaborandi', Br. med. J., occasionally chloral hydrate, or croton chloral
1875, i: 241±2; idem, `On the physiological action hydrate.''
12
of jaborandi', Proc. Cambr. Phil. Soc., 1875, April, For a summary account, see idem, `The
pp. 402±4; idem, `The action of jaborandi on the heart', salivary glands', in E A Schafer (ed.), Text-book of
J. Anat. Physiol., 1875, 10: 187±201. physiology, Edinburgh, Pentland, 1898±1900, vol. 1,
9
Idem, `The action of pilocarpin on the sub- pp. 475±530.
13
maxillary gland of the dog', J. Anat. Physiol., 1876, E Klein, J N Langley and E A Schafer, `On
11: 173±80; idem, `On the physiology of the salivary the cortical areas removed from the brain of a dog,
secretion. Part II. On the mutual antagonism of and from the brain of a monkey', J. Physiol., 1883, 4:
atropin and pilocarpin, having especial reference to 231±47; J N Langley, `The structure of the dog's brain',
their relations in the sub-maxillary gland of the cat', J. Physiol., 1883, 4: 248±85; idem, `Report on the
J. Physiol., 1878, 1: 339±69. parts destroyed on the right side of the brain of the dog
10 The Cruelty to Animals Act, 1876, clauses 3 operated on by Prof. Goltz', J. Physiol., 1883, 4:
and 5. On the history and debate of this piece of 286±309; J N Langley and C S Sherrington, `Secondary
legislation, see R French, Antivivisection and medical degeneration of nerve tracts following removal of
science in Victorian society, Princeton University the cortex of the cerebrum in the dog', J. Physiol., 1884,
Press, 1975; N A Rupke (ed.), Vivisection in historical 5: 49±65; J N Langley and A S Grunbaum, `On the
perspective, London, Routledge, 1990. degeneration resulting from removal of the cerebral
11 For example, Langley, `The action of pilocarpin', cortex and corpora striata in the dog', J. Physiol.,
note 9 above, p. 174 (with reference to experiments 1890, 11: 606±28. For the general context of this
on dogs): ``In every case the animal was placed research, see E Clarke and L S Jacyna, Nineteenth-
under anaesthetics during the operation and killed at century origins of neuroscientific concepts,
its close; the anaesthetics employed have been Berkeley, University of California Press, 1987.

155
 Andreas-Holger Maehle
In 1883 Langley was elected a Fellow of the Royal Society of London, and in 1884 he
took up his new posts as Lecturer in Natural Science at Trinity College and as University
Lecturer in Histology. Over the years Langley assumed the role of Foster's deputy in the
Cambridge Physiological Laboratory. From the late 1880s Langley became interested in the
structure and function of the vegetative or ``involuntary'' nervous system, which had been
examined morphologically and physiologically by his senior colleague Walter Holbrook
Gaskell (1847±1914). In the early 1880s Gaskell had demonstrated the existence of both
inhibitory and accelerator fibres in the vagus nerve of cold-blooded animals, providing in
this way a simple explanation for the wide range of cardiac effects of vagus stimulation that
had puzzled earlier physiologists. Building on this finding, his subsequent research explored
the hypothesis that not only the heart but all involuntary muscles were innervated by two
different, antagonistic types of visceral nerve fibres. By 1886 he had distinguished morpho-
logically the visceral (vegetative) fibres stemming from the thoracic part of the spinal cord
(i.e. the sympathetic system) from the fibres that originated from its cervico-cranial and
sacral regions (i.e. the parasympathetic system). Moreover, Gaskell had pointed out that the
actions of the thoracic part of the vegetative nervous system were antagonistic to the actions
of the other two parts.14
Against this background, a methodically important observation was made by Langley
and a medical collaborator, William Lee Dickinson (1863±1904) of Caius College,
Cambridge. They found that nicotine selectively blocked nervous conduction in sympa-
thetic ganglia, i.e. that it interrupted the transmission of nerve impulses from the pre-
ganglionic to the post-ganglionic nerve fibre. By electrically stimulating the nerve fibres
running to and from a ganglion, before and after local application of a nicotine solution to
the ganglion, it could then be distinguished which fibres ended in the nerve cells of the
ganglion and which simply passed through it.15 In the following years Langley used nicotine
and other drugs as tools for a detailed functional and structural analysis of the sympathetic
and parasympathetic systems, to which he gave the now common collective name
``autonomic nervous system''.16 In 1893 Langley became president of the Neurological
Society of Great Britain and in 1899 president of the Physiological Section of the British
Association for the Advancement of Science. As the new century started, he was an
internationally recognized expert in the research field of the vegetative nervous system.17

14
Cf. Geison, op. cit., note 6 above, pp. 313±19; nomenclature, p. 883); idem, `The sympathetic and
J N Langley, `Walter Holbrook Gaskell, 1847±1914', other related systems of nerves', in Schafer (ed.), op.
Proc. R. Soc. Lond., series B, 1915, 88: xxvii±xxxvi. On cit., note 12 above, vol. 2, pp. 616 ±96; J N Langley,
the history of research into the vegetative nervous `The autonomic nervous system. Presidential address',
system prior to Gaskell and Langley, see Clarke and Brain, 1903, 26: part I, 1±26; idem, `The nomenclature
Jacyna, op. cit., note 13 above, pp. 308±70; and for a of the sympathetic and of the related systems of nerves',
brief summary account, E H Ackerknecht, `The Zentralblatt fur Physiologie, 1913, 27: 149±52; idem,
history of the discovery of the vegetative (autonomic) The autonomic nervous system, part I, Cambridge,
nervous system', Med. Hist., 1974, 18: 1±8. W Heffer & Sons, 1921 (no second part of this
15
J N Langley and W L Dickinson, `On the local monograph appeared).
17
paralysis of peripheral ganglia, and on the connexion Idem, `Das sympathische und verwandte nervoÈse
of different classes of nerve fibres with them', Proc. R. Systeme der Wirbeltiere (autonomes nervoÈses
Soc. Lond., 1889, 46: 423±31. System)', Ergebnisse der Physiologie, 1903, 2:
16
For summary accounts, see J N Langley, part 2, 818±72; idem, `The autonomic nerves',
`Presidential address, Section IÐPhysiology', Report Nederlandsch Tijdschrift voor Geneeskunde, 1905,
of British Association for 1899, pp. 881±92 (on the no. 16, pp. 1013±30.

156
 John Newport Langley and a Receptor Theory of Drug Action
In 1896 he had been awarded an Sc.D., and in 1903 he succeeded Foster to the Chair of
Physiology, having been Deputy Professor of Physiology since 1900.
Back in 1894, he had already taken over the editorial responsibilities for Foster's Journal
of Physiology, saving the periodical in a financial crisis. From then on Langley owned the
Journal, and until the end of his life he edited it with great commitment, often virtually
rewriting other authors' manuscripts. In particular, he insisted that papers were written in
the most efficient format and were thus concise and short. In this way he forcefully promoted
the modern style of scientific writing.18 Langley soon made it to the top of the scientific
establishment. In 1897/8 he served on the Council and in 1904/5 as Vice-President of the
Royal Society.
In 1905 Langley first published, in the Journal of Physiology, his concept of ``receptive
substances''.19 His subsequent work in this area remained part of his research in neuro-
physiology, a field which he continued to cultivate until the end of his life. In the years
leading up to the First World War, Langley oversaw, in addition to his research and teaching
duties, the work on a new building for the School of Physiology, which opened in June
1914.20 Even during the war he was able to keep his research going, studying, for example,
together with Japanese co-workers the phenomena of nerve regeneration and of muscular
atrophy after denervationÐin search of better treatments for injuries.21
Langley was not only fully devoted to his research and his academic duties, but was
also, for most of his life, a keen athlete. His greatest talent here was ice-skating, a sport
in which he even devised official rules and was called upon as an appeal judge in inter-
national competitions.22 Langley died on 5 November 1925, after very brief illness,
at his house in Madingley Road, Cambridge, to which he had moved from Trinity
College after he had married Vera Kathleen Forsythe-Grant in 1902. At the end of his
life he held honorary degrees from the universities of Dublin, St Andrews, Groningen, and
Strasbourg.

Mutual Antagonism of Poisons and its Implications for Drug Action Theory
In the mid-1870s, the young Langley undertook his first original physiological
investigation in connection with Foster's research into the origin of the heartbeat.23 Sydney
Ringer (1835±1910) had given a sample of an alcoholic extract of jaborandi to Foster, who

18 21
Cf. the obituary on Langley by W M Fletcher in J N Langley and T Kato, `The rate of loss of
the Journal of Physiology, note 7 above, pp. 12±13. weight in skeletal muscle after nerve section with some
19
J N Langley, `On the reaction of cells and of observations on the effect of stimulation and other
nerve-endings to certain poisons, chiefly as regards treatment', J. Physiol., 1915, 49: 432±40; J N Langley
the reaction of striated muscle to nicotine and to curari', and M Hashimoto, `On the suture of separate nerve
J. Physiol., 1905, 33: 374±413. For a detailed bundles in a nerve trunk and on internal nerve
discussion of this paper, see below. plexuses', J. Physiol., 1917, 51: 318±45; J N Langley,
20
On Langley's engagement for the new building, `On the separate suture of nerves in nerve trunks',
which was funded by a donation from the Drapers' Br. med. J., 1918, i: 45±7; J N Langley and
Company, see University of Cambridge, Department of M Hashimoto, `Observations on the atrophy of
Manuscripts and University Archives, `The Professor denervated muscle', J. Physiol., 1918, 52: 15±69.
22
of Physiology 1878 to 1925', UA CUR 39.37, pp. 17, Fletcher, `John Newport Langley: in memoriam',
31, and Department of Physiology, `History of Lab note 7 above, pp. 14±15.
23
Building 1912±14 . . . Papers in connection with See Geison, op. cit., note 6 above, pp. 193±235,
building of Physiol. Lab. Box II'. 242±4.

157
 Andreas-Holger Maehle
passed it on to Langley for physiological testing. Langley noted in his animal experiments
(on the dog, rabbit, and frog) a significant slowing of the heartbeat after the drug extract had
been injected. Such an effect could be interpreted as the consequence of a stimulating action
of jaborandi on ``inhibitory fibres'' of the vagus nerve ending in the heart.24 However, this
slowing effect could still be produced after curare had been administered, which was then
widely held to paralyse nerve endings.25 Langley therefore concluded that jaborandi acted
``probably . . . more peripherally than the endings of the vagus nerves''.26
This view conflicted, however, with that of the Paris physician and experimental
pathologist Edme FeÂlix Alfred Vulpian (1826 ±1887), who had proposed that jaborandi
stimulated the endings of inhibitory vagus fibres in the heart, based on experiments in which
curare appeared to prevent jaborandi's slowing effect on the heartbeat.27 Langley was in this
way drawn into a more detailed examination of the drug's cardiac action. In one of his
experiments, described by him as ``perhaps the most decisive'', he curarized an anaesthe-
tized rabbit until respiration almost ceased. Through a tracheotomy, artificial respiration
was maintained. Subsequent electrical stimulation of the peripheral end of the animal's left
vagus nerve no longer had any effect on the heart. Nevertheless, when the rabbit was then
subcutaneously injected with an aqueous extract of jaborandi, a marked decrease of the
frequency of its heartbeats (from 250±270 per minute to 120 per minute) occurred within ten
minutes. This finding confirmed Langley's initial hypothesis that jaborandi ``produces this
slowing by acting on something else than on the inhibitory nerve-fibres going to the
heart''.28
In an earlier series of experiments, on the frog, Langley had found that jaborandi
increased the inhibitory (slowing) effect of vagus stimulation on the heart. However, by
injection or local application of atropine, even hearts that had been stopped in this manner
could be brought back to their rhythmic beat.29 In further experiments on frogs, he invest-
igated this antagonistic action of jaborandi and atropine on the heart. Applying solutions of
the two substances directly to the heart of a frog whose brain and spinal cord had been
destroyed, Langley showed ``that a definite quantity of atropia can only prevent a propor-
tionate definite quantity of jaborandi from producing its effects on the heart'' and ``that the
condition of the heart . . . depends on the relative amounts of jaborandi and atropia pre-
sent''.30 Moreover, the antagonism between the two poisons could also be demonstrated
locally, by way of direct application, in different parts of the heart, for example, only in the
auricles, or the sinus venosus, or the ventricles. This observation suggested to Langley that
the drugs acted directly on the whole neuromuscular tissue of the heartÐnot on some
localized nervous mechanism that caused and controlled the heartbeat.31

24 28
Langley, `Preliminary notice', note 8 above, Ibid., p. 190.
29
p. 242. Langley, `Preliminary notice', note 8 above,
25
This view on the mode of action of curare went p. 242; idem, `On the physiological action of
back to experiments by Claude Bernard in the 1840s jaborandi', note 8 above, pp. 403±4.
30
and 1850s. See J M D Olmsted, Claude Bernard, Idem, `The action of jaborandi on the heart',
physiologist, London, Cassell, 1939, pp. 223±8. note 8 above, pp. 194±5.
26 31
Langley, `On the physiological action of Cf. ibid., pp. 197±8.
jaborandi', note 8 above, p. 404.
27
Cf. Geison, op. cit., note 6 above, p. 242;
Langley, `The action of jaborandi on the heart',
note 8 above, p. 189.

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 John Newport Langley and a Receptor Theory of Drug Action
In this way Langley's study supported Foster's view that the heartbeat had a muscular, not
a nervous origin.32 Yet, this was not its only significance. At the very start of his research
career Langley had hit upon a problem that would recur time and time again in the course of
his experimental work and that ultimately led him to his theory of receptive substances: do
drugs act directly on the effector cells (in this case, the heart cells) or do they primarily affect
the endings of nerves terminating in the organ tissues? Moreover, how do drugs combine
with the tissues that they affect? And how do they cause changes in the cell's function? At
the time, the young Langley believed that an action of jaborandi on the muscle tissue alone,
and not at all on nerve cells, was ``a supposition very difficult to accept''.33 But he did
recognize that the problem required further investigation.
In his next series of experiments Langley was able to use the alkaloid pilocarpine, which
had been isolated from jaborandi bark and leaves in 1875.34 Jaborandi was known to
produce salivation in human beings and higher animals.35 In experiments on the sub-
maxillary gland of the dog Langley showed that pilocarpine and atropine acted as mutual
antagonists with regard to salivary secretion: the secretion caused by pilocarpine could be
stopped through atropine, restarted by pilocarpine, stopped again by atropine, and so on.
Comparing this with his earlier findings, he concluded that ``the secretion or absence of
secretion is dependent on the relative quantity of the two poisons present, just as is the stand-
still or beat of the heart''.36
In 1877, the Zurich physiologist Balthasar Luchsinger (1849±1886) published an
experimental study on the antagonism between pilocarpine and atropine on the secretion
of sweatglandsinthecat.Luchsinger gavea verygraphic description ofthemutualantagonism
between the two alkaloids by stating that their actions combined algebraically ``like wave
crests and hollows, like plus and minus''.37 Langley's interest was immediately aroused, as
this appeared to be a parallel case to his own observations on the antagonistic effects of
pilocarpine and atropine on the salivary secretion of the dog. In further experiments, on the
sub-maxillary gland of the cat, Langley found that this antagonism was not quite as simple as
Luchsinger had described it. The mutual antagonism was dose-dependent and thus incom-
plete. If large doses of atropine had been applied, pilocarpine could produce secretion less
fully; and when very large doses of pilocarpine were administered, this did not produce
secretion, and this condition could not be antagonized by atropine. Nevertheless, Langley
followed Luchsinger in an essential point. The Swiss researcher had concluded that the effect
of the antagonism between the two alkaloids depended ``simply and solely upon the relative
number of the poison molecules present'' and that the antagonistic alkaloids bound
chemically to the ``living protein'' (protoplasm) of the cell. In this way compounds between

32
Geison, op. cit., note 6 above, p. 242. p. 132; and Langley, `Preliminary notice', note 8 above,
33
Langley, `The action of jaborandi on the heart', p. 242.
36
note 8 above, p. 198. Langley, `The action of pilocarpin', note 9 above,
34
Pilocarpine was isolated by A W Gerrard of p. 180.
37
University College Hospital, London; see `The alkaloid B Luchsinger, `Die Wirkungen von Pilocarpin
of jaborandi', Chemist and Druggist, 1875, June 15, und Atropin auf die Schweissdrusen der Katze. Ein
p. 192. Beitrag zur Lehre vom doppelseitigen Antagonismus
35
See, for example, experiments with jaborandi on zweier Gifte', Pfl
uger's Archiv f ur Anatomie und
the sub-maxillary gland of the dog described in Physiologie, 1877, 15: 482±92, on p. 488. Quotation in
`Vulpian on the action of jaborandi and atropia on Langley's translation, cf. Langley, `On the physiology
perspiration', London Medical Record, 1875, March 3, of the salivary secretion', note 9 above, p. 339.

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 Andreas-Holger Maehle
either the stimulating or the inhibiting poison and the cell's protein molecules were formed,
depending on the mass of each poison present and their relative affinity to the protoplasm.38
While Langley was still unsure about the question whether the poisons acted on the nerve
endings in the salivary gland or on the gland cells themselves, he elaborated on Luchsinger's
idea of a chemical union between drug molecules and cell components:
. . . we may, I think, without much rashness, assume that there is some substance or substances in
the nerve endings or gland cells with which atropin and pilocarpin are capable of forming
compounds. On this assumption then the atropin or pilocarpin compounds are formed according to
some law of which their relative mass and chemical affinity for the substances are factors. In the
analogous case with inorganic substances, other things being equal, these are the sole factors. To
take the simplest case, if a and b are both able to form, with y, the compounds ay, by, then ay and by
are both formed, quantity of ay and by depending on the relative masses of a and b present and their
relative chemical affinity to y.39
Langley realized that, in view of the incomplete antagonism between pilocarpine and
atropine, the laws for the formation of inorganic compounds were only applicable to this
case with ``some modification'', but he was convinced that ``the action of mass'' had been
``clearly shown'' in his study.40 Without doubt, his later ideas on receptive substances and
on chemical binding between drugs and cells were foreshadowed in these remarkable
considerations of the late 1870s.
During the following ten years Langley was largely preoccupied with the physiology and
histology of glands, working in this field with rigorous precision and sense for detail.41 Yet
he also kept an interest in the questions of drug antagonism. This interest was particularly
fuelled by the work of the W urzburg pharmacologist Michael Joseph Rossbach
(1842±1894), who attacked the theory of a mutual antagonism between certain poisons.
According to Rossbach, a tissue once paralysed by an alkaloid could not be restored to its
former condition by applying another alkaloid. In experiments likewise carried out on the
sub-maxillary salivary gland (of the dog), the Wurzburg scientist had found that
the stoppage of secretion through atropine could be overcome by physostigmine only if
the atropine dose had been small. He explained this with the hypothesis that the alkaloids
had two points of attack on the gland: the nervous part and the glandular part. Small doses of
atropine were thought to paralyse merely the nerve for secretion, i.e. the chorda tympani,
leaving the gland cells unaffected. In this case, physostigmine could then still produce a
flow of saliva by stimulating the gland cells. If however a large dose of atropine was given,
nerve fibres as well as gland cells would be paralysed, so that physostigmine would then
be unable to restore secretion.42
Langley, using pilocarpine instead of physostigmine as the stimulating agent, provided
experimental evidence against Rossbach's view. Experimenting on the sub-maxillary gland

38 42
Luchsinger, op. cit., note 37 above, pp. 488, M J Rossbach, `Neue Studien uber den
491±2. physiologischen Antagonismus der Gifte', Pfl
uger's
39
Langley, `On the physiology of the salivary Archiv f
ur Anatomie und Physiologie, 1879, 21: 1±38,
secretion', note 9 above, p. 367. on pp. 33±8.
40
Ibid.
41
For a list of Langley's publications in this area,
see Fletcher, `John Newport Langley: in memoriam',
note 7 above, pp. 16±18.

160
 John Newport Langley and a Receptor Theory of Drug Action
of the anaesthetized cat, he paralysed the chorda tympani by intravenous injection of
atropine: electrical stimulation of the nerve no longer led to salivary secretion. He then
restored the secretion by injection of pilocarpine into the duct of the gland, and stopped the
salivary flow again by giving intravenously another dose of atropine. According to
Rossbach's interpretation, this second dose of atropine would have paralysed the gland
cells. Nevertheless, Langley could again produce secretion by injecting more pilocarpine,
and even after this flow had been stopped again by atropine, yet more pilocarpine could still
restore itÐwhile the chorda tympani remained paralysed throughout.43
On the basis of these findings Langley held on to his view that there was a mutual
antagonism (within a certain dose range) between the two poisons, pilocarpine and atropine.
They acted on the same tissue, forming ``chemical compounds'' with it, and the result
depended ``on their relative chemical affinity to the tissue and the mass of each present''.44

Experiments with Nicotine and Adrenalin

Those pharmacological issues, which Langley had addressed in his work on the heartbeat
and on glandular secretion, emerged again in the 1890s, in the new context of his research on
the autonomic nervous system. As mentioned above, Langley and Dickinson had recog-
nized, in 1889, that nicotine poisoning could be used as an investigative tool in the analysis
of the sympathetic system, because it selectively paralysed the nerve cells of sympathetic
ganglia.45 A question that was linked with this finding was whether other poisons likewise
affected nerve cells, or rather the endings of nerve fibres. From experiments on frog hearts,
Langley and Dickinson concluded that nicotine acted upon nerve cells in the heart, whereas
muscarine and its antagonist atropine appeared to exert their effects on the peripheral
endings of the vagus fibres leading to the heart.46 In a further series of trials they tested
several other alkaloids and poisons, including picrotoxin, apomorphine, codeine, cocaine,
curarine, brucine, and strychnine, in view of their point of attack, i.e. nerve cell body or
nerve ending, by examining their effect on the superior cervical ganglion and on the cervical
sympathetic of the anaesthetized rabbit. More generally, Langley and Dickinson also hoped
to uncover differences in the poisons' mode of action that might open up ``a new line of
physiological investigation''. However, there were inconsistencies between the effects
observed after local application and after intravenous injection. Nicotine remained the
clearest example of a poison that seemed to affect nerve cells (i.e. the cell body) rather
than the endings of nerve fibres.47

43 46
J N Langley, `On the antagonism of poisons', J N Langley and W L Dickinson, `Pituri and
J. Physiol., 1880, 3: 11±21. nicotin', J. Physiol., 1890, 11: 265±306.
44 47
Ibid., p. 19. J N Langley and W L Dickinson, `Action of
45
Langley and Dickinson, op. cit., note 15 above. various poisons upon nerve-fibres and peripheral
See also J N Langley and W L Dickinson, `On the nerve-cells', J. Physiol., 1890, 11: 501±27. On the
progressive paralysis of the different classes of nerve tradition of physiological experimentation with
cells in the superior cervical ganglion', Proc. R. Soc. alkaloids, going back to the work of FrancËois
Lond., 1890, 47: 379±90; J N Langley and Magendie, see J E Lesch, Science and medicine in
H K Anderson, `The action of nicotine on the ciliary France: the emergence of experimental physiology,
ganglion and on the endings of the third cranial nerve', 1790±1855, Cambridge, MA, Harvard University
J. Physiol., 1892, 13: 460±8. Press, 1984.

161
 Andreas-Holger Maehle
As the histological work of Santiago RamoÂn y Cajal (1852±1934), Rudolf von Koelliker
(1817±1905) and others provided evidence for a discontinuity between nerve endings and
nerve cells,48 Langley began to doubt his former interpretation and tended to believe that
nicotine did not actually affect the nerve cells in the ganglion but rather the endings of the
pre-ganglionic fibres that terminated close to them.49 However, after cutting the pre-
ganglionic nerve fibres and allowing them to degenerate for up to twenty-six days,
local application of nicotine to the superior cervical ganglion still caused its characteristic
effects. This experimental result, reported by Langley in 1901, seemed to confirm the
exceptional role of nicotine as a substance attacking nerve cells rather than the endings
of nerve fibres.50
Though favouring the new neurone theory over the old concept of a continuous network
of nerve fibres and nerve cells, Langley kept an open mind on this more general issue.
He adopted the terminology of the new theory, ``because the facts cannot be expressed in
terms of both theories without extraordinary verbiage''. Believing in independence of
histological and of physiological evidence, Langley held that even in the event that the
neurone theory would have to be abandoned, his physiological observations would still
remain valid.51
Yet, the issue of the precise point of attack of a drug or poison was brought up again at this
time through the new physiological research with extracts of the suprarenal gland (contain-
ing adrenaline), in the wake of the pioneer study in this field by the Harrogate physician
George Oliver (1841±1915) and the Professor of Physiology at University College London,
Edward Albert Schafer (1850±1935). One observation made by Oliver and Schafer, which
became particularly important for Langley, was that suprarenal extract seemed to produce
the typical rise in arterial blood pressure by directly acting on the smooth (unstriated)
muscle tissue of the blood vessels. When Oliver and Schafer added suprarenal extract
to the perfused arterial system of frogs whose central nervous system had been destroyed,
the arterioles contracted so much that the flow of the circulating perfusion fluid came almost
to a standstill. Moreover, when the brachial nervous plexus of an anaesthetized dog was
cut on one side, but left intact on the other side, intravenous injection of suprarenal
extract caused equally on both forearms a prolonged diminution of size (measured with
a plethysmograph). Also this spoke for a direct action of the extract on the muscle tissue of
the arterioles, rather than for an effect on nerves.52 German physiologists soon reported
other experimental findings that likewise supported the view that suprarenal extract acted
directly on muscle tissue, not on nerve endings. Max Lewandowsky (1876±1918) of the
Physiological Institute in Berlin showed in an experiment on the cat that the extract
continued to produce contraction of the smooth muscles of the eye and eye socket (inner-
vated by sympathetic nerves) even after the sympathetic cervical ganglia had been excised
and the post-ganglionic nerve fibres allowed to degenerate.53 Moreover, by expanding upon
48 52
For a recent summary of the origins of the G Oliver and E A Schafer, `The physiological
discontinuity or neurone theory, see Robinson, effects of extracts of the suprarenal capsules',
op. cit., note 1 above, pp. 1±30. J. Physiol., 1895, 18: 230±76, on pp. 239, 245±7.
49
J N Langley, `On the stimulation and paralysis 53 M Lewandowsky, `Ueber die Wirkung des

of nerve-cells and of nerve-endings. Part I', J. Physiol., Nebennierenextractes auf die glatten Muskeln,
1901, 27: 224±36, on p. 224. im Besonderen des Auges', Pfl uger's Archiv fur
50
Ibid., p. 229. Anatomie und Physiologie, 1899, pp. 360±6.
51
Cf. ibid., pp. 224±5.

162
 John Newport Langley and a Receptor Theory of Drug Action
experiments made by Oliver and Schafer, the GoÈttingen physiologist Heinrich Boruttau
(1869±1923) demonstrated that suprarenal extract also acted directly on somatic striated
muscle tissueÐnot on motor nerve fibres.54
For Langley, this all meant that there was apparently a second substance, besides nicotine,
that directly affected cells rather than nerve endings. He repeated Lewandowsky's experi-
ment on the cat's eye and was able to confirm his findings.55 He also returned to his tried and
tested experimental model, the sub-maxillary gland of the cat, and found that suprarenal
extract caused secretion even after the superior cervical ganglion had been removed and ten
days had been allowed for the post-ganglionic secretory nerve fibres to degenerate.56 These
results spoke for a direct action on the effector cells, i.e. the muscle cells and gland cells,
respectively.
Langley was probably the first who pointed out the striking parallels between the effects
of suprarenal extract and of electrical stimulation of sympathetic nerves.57 There were,
however, considerable differences in the effect of suprarenal extract on various tissues
innervated by autonomic nerve fibres. Differences occurred also in the effect of nicotine on
ganglia. It paralysed the upper cervical ganglia and the ganglia of the lateral chain more
easily than those of the solar plexus. Moreover, there were differences in nicotine's efficacy
between related species, such as dogs and cats, and even between individual animals of the
same species. Langley speculated that the reaction to nicotine depended ``upon the presence
of a special chemical substance in the nerve-cells or on the nerve-endings'', and that there
had to be differences ``in the chemical constitution of protoplasm'' that were responsible for
the alkaloid's varying efficacy in different animals. Without naming Paul Ehrlich, or any
other researcher in the nascent field of immunology, Langley drew attention to ``recent
investigation[s] upon toxins and anti-toxins'', which had shown ``what enormous effects on
the organism these differences in chemical constitution may bring about''.58
In these speculative remarks, made in 1903, Langley had come very close to the idea of
drug receptors in cells. In fact, two years later he was to formulate his concept of ``receptive
substances''. In the meantime, however, a student of Langley, Thomas Renton Elliott
(1877±1961), had taken up his professor's observation of the parallelism of effect between
suprarenal extract and sympathetic nerve stimulation.

The Idea of Receptive Substances

Working with ``adrenalin'', which had been isolated from suprarenal glands by Jokichi
Takamine (1854±1922) in 1901, Elliott provided further examples of ``the broad rule that
the action of the substance [i.e. suprarenal extract] upon plain muscle simulates
that of electrical excitation of the sympathetic nerves supplying each particular

54
H Boruttau, `Erfahrungen uber die Nebennieren', neurotransmission. In 1946 Ulf Svante von Euler
Archiv fur die gesamte Physiologie, 1899, 78: provided persuasive evidence that noradrenaline
97±128, on pp. 109±11. was the transmitter substance of sympathetic
55 J N Langley, `Observations on the physiological nerves. See Robinson, op. cit., note 1 above,
action of extracts of the supra-renal bodies', pp. 56, 123±4; Dupont, op. cit., note 1 above,
J. Physiol., 1901, 27: 237±56, on pp. 244±5. pp. 46, 173±4.
56 58
Ibid., pp. 241±2. J N Langley, `The autonomic nervous system.
57
Ibid., p. 256. This observation places Langley Presidential address', note 16 above, pp. 6±7.
also in the history of the discovery of chemical

163
 Andreas-Holger Maehle
muscle''.59 He also investigated some apparent exceptions to this rule. In May 1904, in a
preliminary communication to the Physiological Society, the young researcher made hisÐ
today famousÐsuggestion, that adrenalin was ``secreted by the sympathetic paraganglia''
and might be ``the chemical stimulant liberated on each occasion when the [nervous]
impulse arrives at the periphery''.60 While this proposal has placed Elliott firmly in the
history of the concept of chemical neurotransmission,61 his thoughts on how the muscle cell
received the stimulus of the ``chemical excitant'', and reacted with a change of tension of the
muscle fibres, were important for the development of the receptor idea.
Langley and Lewandowsky had been criticized for their view that suprarenal extract
acted directly on muscle cells by Thomas Gregor Brodie (1866 ±1916), Professor-
Superintendent of the Brown Institution, and Walter Ernest Dixon (1871±1931), then
Assistant to the Downing Professor of Medicine at Cambridge. Reporting their own experi-
ments and experimental results obtained by other researchers, Brodie and Dixon argued that
adrenalin affected the sympathetic nerve endings, not the peripheral tissues themselves. In
particular, they suspected that Langley and Lewandowsky had not allowed enough time in
their degeneration experiments for the sympathetic nerve endings completely to disappear
before the suprarenal extract was tested.62 Elliott addressed this criticism. In an experiment
on a cat, he excised the ciliary and superior cervical ganglion of the left side. Nearly ten
months later he tested the effect of intravenous injection of adrenalin on the animal's iris:
the typical dilation of the pupil appeared even more quickly and was more extensive on
the operated side than on the normal side. In Elliott's mind there was no doubt that the
sympathetic nerve endings had entirely degenerated after such a long time and that the
adrenalin therefore could not have acted on them.63
Another critical argument, brought forward by Brodie and Dixon, came from an
experiment that the latter had made with apocodeine. Dixon had shown that the contraction
of the muscle tissue of blood vessels that was typically produced by adrenalin could be
almost completely prevented by previous injection of apocodeine. Yet, subsequent injection
of barium chloride still led to vasoconstriction. This meant (for Brodie and Dixon) that the
muscle tissue as such had not been injured by the apocodeine, and that therefore both
apocodeine and adrenalin had acted on the nerve endings terminating in the blood vessels.64
Against this background of conflicting experimental evidence Elliott suggested that it
was neither the nerve endings nor the contractile fibres of the muscle cell that were affected
by adrenalin. He proposed instead that the ``substance'' that was excited by adrenalin was
the ``myoneural junction'', i.e. the link between nerve ending and muscle cell, which he
believed to originate from, and to be sustained by, the muscle cell. This hypothesis

59 62
T R Elliott, `The action of adrenalin', J. Physiol., T G Brodie and W E Dixon, `Contributions
1905, 32: 401±67, on p. 402. On the identification of the to the physiology of the lungs. Part II. On the
active principle of the suprarenal glands, see innervation of the pulmonary blood vessels; and
E M Tansey, `What's in a name? Henry Dale and some observations on the action of suprarenal
adrenaline, 1906', Med. Hist., 1995, 39: 459±76, on extract', J. Physiol., 1904, 30: 476±502, on
pp. 465±6, 472±3. pp. 500±1.
60 63
T R Elliott, `On the action of adrenalin', Elliott, op. cit., note 59 above, pp. 431±2.
64
J. Physiol., 1904, 31: xx±xxi, on p. xxi. Brodie and Dixon, op. cit., note 62 above,
61
See Robinson, op. cit., note 1 above, pp. 56±9; pp. 497±8.
Bennett, op. cit., note 5 above, pp. 530±1; Dupont,
op. cit., note 1 above, p. 47.

164
 John Newport Langley and a Receptor Theory of Drug Action
explained for him also why adrenalin affected only those tissues that had a sympathetic
innervation. The union with sympathetic nerves during phylogenetic development, he
believed, led in the muscle cells to the growth of a special ``substance'' which could be
excited by adrenalin. The nature of this substance, i.e. of the myoneural junction, deter-
mined whether the impulse travelling down a sympathetic nerve led to contraction or
inhibition (relaxation) of the muscle fibres. In this way the differences in adrenalin's action
in different tissues could be explained.65 Moreover, Elliott speculated that the other parts of
the autonomic nervous system, i.e. the parasympathetic nerves and the autonomic ganglia,
and also the skeletal nerves leading to striated muscle, had a different type of junction from
that in the sympathetic nerves.66 From these considerations, it was only a very small step for
Elliott's teacher Langley, who probably guided his student's thoughts in this difficult and
controversial matter,67 to formulate the concept of ``receptive substances''.
In December 1905, in his classic paper on ``receptive substances'', Langley critically
reviewed the evidence that had so far been provided on the direct action of certain drugs
and poisons on cells. In particular the experiments involving degeneration of the nerve
fibres before a drug's effects were tested, as carried out by Lewandowsky, Elliott, and
himself, appeared crucial to him. In the light of Brodie's and Dixon's criticism, Langley
gave details of another experiment of his own on a cat, in which he showed that an extract
made from ``Burroughs and Wellcome's supra-renal tabloids'' produced the typical adren-
alin effects on the head (eyes, sub-maxillary gland etc.) fourteen and a half months after the
superior cervical ganglion had been excised. The point that certain poisons acted directly on
cells, for example, nicotine on nerve cells, or adrenalin, pilocarpine and atropine on
unstriated muscle cells and gland cells, seemed now to him quite well established.68
There remained, however, two problems that required a more differentiated account of
the drugs' mode of action.
The first problem was that the efficacy of adrenalin on unstriated muscle differed
considerably between the various tissues in the body, even between tissues that were
innervated by the sympathetic nervous system. The second problem was Dixon's finding
that apocodeine prevented the vascular constricting action of adrenalin, but not that of
barium chloride, which suggested that adrenalin acted on nerve fibres, not on muscle fibres.
In response to these problems Langley proposed that adrenalin did not directly stimulate the
muscle cell's ``contractile substance qu^a contractile substance'', but that it acted on ``acces-
sory protoplasmic substances'' of the cell. Intrinsic differences in these accessory
substances could explain the differences in adrenalin's efficacy on various (unstriated)
muscle tissues.69
Langley next turned to nicotine and its effect on striated, skeletal muscle to further
support this hypothesis. In the anaesthetized fowl, intravenous injection of nicotine caused

65 67
Elliott, op. cit., note 59 above, pp. 434±7. Elliott acknowledged his ``indebtedness for
66
Ibid., p. 437±8. On the history of the advice'' to Langley, but also to Gaskell and
identification of acetylcholine as the transmitter in H K Anderson. Elliott, op. cit., note 59 above, p. 467.
68
these other synapses, see Robinson, op. cit., note 1 Langley, op. cit., note 19 above, pp. 374±80.
above, pp. 55±68, 70±6; Dupont, op. cit, note 1 above; On the preparation of the tabloid extract, idem,
E M Tansey, `Sir Henry Dale and autopharmacology: op. cit., note 55 above, p. 237.
the role of acetylcholine in neurotransmission', in 69 Idem, op. cit., note 19 above, pp. 375±6.

C Debru (ed.), Essays in the history of the physiological

sciences, Amsterdam, Rodopi, 1995, pp. 179±93.

165
 Andreas-Holger Maehle
a characteristic prolonged, tonic contraction of the gastrocnemius muscle of the leg, even
after the sciatic and internal peroneal nerve had been cut in order to exclude any central
nervous influence. Also when the internal peroneal nerve had been ``paralysed'' through
nicotine (i.e. when electric stimulation of the nerve no longer led to a muscular contraction),
a larger dose of nicotine still caused the gastrocnemius to contract. This indicated that
nicotine acted then directly on muscle cells. Intravenous injection of curare abolished the
nicotine-induced tonic contraction, and further injection of nicotine brought it on again, i.e.
the two poisons acted as mutual antagonists. As Langley pointed out, the relation between
nicotine and curare was the same as the relation between pilocarpine and atropine, which he
had described twenty-seven years earlier in his experiments on the sub-maxillary gland.
Accordingly, he suggested that nicotine and curare acted upon the same ``protoplasmic
substance or substances'' of the muscle cell. Whether these substances combined pre-
dominantly with nicotine (resulting in stimulation) or with curare (leading to relaxation)
depended on ``the relative amount of the two poisons'' present.70
In the next series of experiments Langley cut the peroneal nerve, excised a piece of it, and
allowed periods of between 6 and 40 days for the peripheral part of the nerve to degenerate.
Functional regeneration was excluded in tests with electro-stimulation of the proximal part of
the cut nerve, and the degeneration of the nerve endings was confirmed in histological
examinations. Yet, injection of nicotine still produced the typical tonic contraction, the
responsiveness of the muscle to the poison actually being increased; and curare still exerted
its antagonistic effect on the nicotine contraction. Moreover, direct electrical stimulation of
the muscle after injection of nicotine or after injection of curare could still produce some
contraction.71
From these observations Langley drew the critical conclusion that ``neither the poisons
nor the nervous impulse act directly on the contractile substance of the muscle but on some
accessory substance'', and he continued: ``Since this accessory substance is the recipient of
stimuli which it transfers to the contractile material, we may speak of it as the receptive
substance of the muscle.''72 Referring briefly to Ehrlich's side chain theory of immunity
(see below), Langley speculated that a receptive substance might be ``a side chain molecule
of the molecule of contractile substance''. He remained cautious though, adding that to him
there seemed to be no advantage at present in ``attempting to refer the phenomena to
molecular arrangement''.73
However, having produced evidence for the action of adrenalin as well as of nicotine and
curare on ``accessory'' or ``receptive'' substances of the cell, Langley dared to generalize.
He suggested that alkaloids such as pilocarpine, atropine, and strychnine, likewise acted in
this manner, as might other internally secreted substances (i.e. hormones), such as secretin,
thyroidin, and ``the various stimulating chemical bodies formed by the generative
organs''.74 More than this, Langley proposed a general rule:

So we may suppose that in all cells two constituents at least are to be distinguished, a chief
substance, which is concerned with the chief function of the cell as contraction and secretion, and

70 73
Ibid., pp. 380±93. Ibid., pp. 399±400.
71 74
Ibid., pp. 393±9. Ibid., p. 400.
72
Ibid., p. 399.

166
 John Newport Langley and a Receptor Theory of Drug Action
receptive substances which are acted upon by chemical bodies and in certain cases by nervous
stimuli. The receptive substance affects or is capable of affecting the metabolism of the chief
substance.75
With these conclusions Langley had laid the foundations of the theory of drug receptors in
cells. He had also made a fundamental contribution to the further development of basic
physiology, as the receptor idea became central to our modern understanding of endogenous
neural, endocrine and immune regulation. Significantly though, Langley located his
``receptive substances'' in the cell rather than on the cell. In this respect his receptor concept
was quite different from the modern one, which describes receptors within the cell as well as
in the membrane.
Obviously, Langley's ``receptive substances'' had resemblances to Ehrlich's ``side
chains'' that would bind bacterial toxins to the cell and which (when produced in excess)
would be separated from the cell to act as anti-toxins or antibodies in the blood. But when
Langley formulated his concept of receptive substances in 1905, Ehrlich still believed that
the side chain theory was applicable only to toxins, not to drugs, chiefly because drugs did
not seem to be firmly fixed in the tissues and could easily be washed out of them by
solvents.76 Langley, on the other hand, did think of a chemical union between the cell's
receptive substances and the drug. Returning to the analogy with binding in inorganic
chemistry that he had used in his discussion of pilocarpine and atropine, he spoke now
of the formation of ``nicotine-muscle compounds'' and ``curare-muscle compounds''.
Which of these two kinds of compounds prevailed depended ``upon the mass of each poison
present and the relative chemical affinities for the muscle radicle [i.e. the receptive sub-
stance or side chain]''. Moreover, he speculated that the biological effect of either con-
traction (through binding of nicotine) or inhibition (through binding of curare) was caused
by different ``chemical re-arrangements set up in the muscle molecule by the combination of
one of its radicles''.77 It was only in 1907, partly due to Langley's work on receptive
substances and alkaloids, that Ehrlich changed his mind and proposed the existence of
``chemoreceptors'' for drugs.78
Langley's receptor concept also had obvious similarities with Elliott's concept of the
``myoneural junction'' that was thought to be acted upon by a nervous impulse or chemical
stimulant. In fact, Langley acknowledged that Elliott's work on adrenalin especially had
``made the issues clearer'' for him.79 He also agreed with Elliott's hypothesis that it was the
nature of the myoneural junction that determined whether a nerve impulse resulted in
contraction or inhibition. Langley suggested that a cell could make two kinds of receptive
substances, ``motor'' and ``inhibitory'', and that the effect of a nervous impulse on the cell
depended on the proportion of these two receptor types.80
However, he disagreed with his student about how the receptive substances may have
been formed and how they had obtained their characteristics during phylogeny. According

75
Ibid., p. 411. cells', Proc. R. Soc. Lond., series B, 1906, 78:
76
See Parascandola and Jasensky, op. cit., note 2 170±94, on p. 181.
78
above, pp. 205±10. For a full discussion of Parascandola and Jasensky, op. cit., note 2
Ehrlich's side chain theory of antibody formation, above, pp. 210±11.
79
see Silverstein, op. cit., note 3 above, pp. 77±94. Langley, op. cit., note 19 above, p. 412.
77 80
J N Langley, `Croonian Lecture, 1906.ÐOn Ibid.
nerve endings and on special excitable substances in

167
 Andreas-Holger Maehle
to Elliott, in developing a union with nerve endings, the cell grows a specific myoneural
junction. On this supposition, Langley expected that in the nerve-degeneration experiments
the myoneural junction, or the receptive substance, degenerated as well, leading to a
diminished physiological response to the application of drugs. But as the experiments
with adrenalin and nicotine had shown, cells were even more sensitive to the drugs
after denervation. Langley had also performed some experiments with adrenalin, nicotine,
and strychnine on chicken embryos, which showed in very early developmental stages quite
marked effects and therefore did not support Elliott's suggestion. Finally, the variety of
effects caused by sympathetic nerve stimulation and adrenalin in various tissues, and the
incomplete parallelism between the two, spoke in Langley's view against Elliott's simple
explanation. As Langley saw it, the various body cells had a constant tendency to vary in
their chemical composition, which upon the formation of a functional connection with a
nerve merely became ``fixed''. Different parts of the nervous system formed their connec-
tion with the peripheral tissues at different periods of phylogenetic development. In this way
different types of receptive or ``synaptic'' substances were established.81
Yet Elliott did not agree with this interpretation. In a subsequent study on the innervation
of the bladder in various animal species, he called his teacher's theory of receptive sub-
stances ``a doctrine of inflexibility''. In particular, he criticized Langley for attributing too
little influence to the nature of the nerves that entered the tissues during phylogeny and had
put too much emphasis on independent chemical changes of the peripheral (muscle) cells.
As Elliott expressed it, Langley's view did ``not clearly ascribe a determinant value to the
entering nerve, which must knock patiently unheard until the cell chances to develope [sic]
the proper receptive substance''.82 However, by the time this criticism was published, in
1907, Elliott had already left Cambridge for his clinical education at University College
Hospital, London, and this specific debate between the two researchers seems to have been
discontinued.83

Criticisms and Further Development of Langley's Receptor Concept

On 24 May 1906 Langley gave the Croonian Lecture to the Royal Society on the topic of
his new concept of receptive substances, adding some more experiments with nicotine and
curare, made on the frog and toad.84 Immediately afterwards he visited the European
continent further to disseminate his ideas. On 28 May he spoke to the Morphological-
Physiological Society of Vienna about ``Nerve endings and special receptive substances in
cells''.85 In the following year, 1907, Langley presented his receptor concept at the Seventh
International Congress of Physiologists in Heidelberg. Reporting experiments with local
application of nicotine solutions to various muscles of the frog, he elaborated upon his
evidence for different kinds of receptive substances. The results of these trials, which

81
Ibid., pp. 405±10, 413. See also Langley, of the Royal Society, 1961, 7: 53±74, on
op. cit., note 77 above, p. 193. pp. 65±6.
82 84
T R Elliott, `The innervation of the bladder Langley, op. cit., note 77 above, pp. 185±8.
and urethra', J. Physiol., 1907, 35: 367±445, on 85 È ber Nervenendigungen und spezielle
Idem, `U
p. 442. rezeptive Substanzen in Zellen', Zentralblatt fur
83
Cf. H H Dale, `Thomas Renton Elliott Physiologie, 1906, 20: 290±1.
1877±1961', Biographical Memoirs of Fellows

168
 John Newport Langley and a Receptor Theory of Drug Action
included also tests on denervated muscles and with the antagonist curare, indicated that the
frog muscle had at least two types of receptive substances for nicotine: one leading to a slow
and prolonged (``tonic'') contraction, and the other causing a rapid and brief contraction
(``fibrillar twitching''). Both types could be located in the region of nerve endings as well as
in other parts of the muscle fibre. Since local application of veratrine caused yet another
pattern of contraction, Langley presumed that there had to be further types of receptive
substances in the muscle. In general, he considered these substances to be radicles of the
contractile molecule of the muscle cell, and he suggested that those near the nerve endings
might have undergone a special development.86
However, Langley's arguments for the existence of receptive substances in cells
encountered quickly the criticism of other researchers. At the same Congress of
Physiologists he was confronted with a critical paper by one of his former collaborators,
Rudolf Magnus (1873±1927), who was then a lecturer in the Pharmacological Institute of
Heidelberg University.87 Magnus focused on one of Langley's key arguments for receptive
substances: the mutual antagonism of nicotine and curare on the denervated muscle. The
Heidelberg pharmacologist acknowledged the general validity of the method of testing
poisons after degeneration of nerves, in order to establish whether or not they acted on the
peripheral tissues or on nerve endings. But he was not convinced that the mutual antagonism
between two poisons actually said something about their specific point of attack. Langley
had concluded that curare bound, like nicotine, to receptive substances of the muscle cells,
because he had found that curare abolished the nicotine-induced contraction of the dener-
vated muscle. Magnus reported against this his own experiments on the muscle of the rabbit,
in which the relevant nerves had been cut and allowed to degenerate. In these trials he used
physostigmine instead of nicotine as the stimulant agent and antagonist of curare. He found
that physostigmine failed to produce a contraction in the denervated muscle from the
twenty-seventh day after section of the nerves. This spoke for an action on nerve endings
and, according to Langley's logic, the antagonist curare would therefore also act on nerve
endings. This example showed, according to Magnus, that the conclusion about the point of
attack on curare depended on which antagonist had been used. If one used nicotine, as
Langley had done, the evidence suggested that curare acted on the muscle cell. If one used
physostigmine, like Magnus, one was led to conclude that curare affected the nerve endings.
In other words, ``nothing at all'' could be found out about a poison's point of attack from
trials with its antagonists. Magnus politely emphasized that he did not wish to criticize
Langley's doctrine of receptive substances as such, but he made it clear that one of the

86
Idem, `Nouvelles observations sur la nature the Netherlands. See O Magnus, Rudolf Magnus,
non-speÂcifique des terminaisons nerveuses motrices physiologist and pharmacologist, 1873±1927, ed.
et sur l'existence de radicules «reÂceptives» dans le L M Schoonhoven, Amsterdam, Koninklijke
muscle', Archives Internationales de Physiologie, Nederlandse Akademie van Wetenschappen, and
1907, 5 : 115±8. A full account of the experiments Dordrecht, Kluwer Academic Publishers, 2002.
underlying Langley's theory of two kinds of nicotine Magnus' joint work with Langley in the Cambridge
receptors is given in idem, `On the contraction of Physiological Laboratory was published as: J N
muscle, chiefly in relation to the presence of Langley and R Magnus, `Some observations of the
``receptive'' substances', J. Physiol., 1907, 36: 347±84; movements of the intestine before and after
1908, 37: 165±212; 285±300; 1909, 39: 235±95. degenerative section of the mesenteric nerves',
87
In 1908 Magnus became professor in Utrecht, J. Physiol., 1905, 33: 34±51.
where he founded the first pharmacological institute of

169
 Andreas-Holger Maehle
Cambridge professor's ``proofs'' for it, the mutual antagonism between nicotine and curare
on the denervated muscle, had to be discounted.88
In the discussion following Langley's and Magnus' presentations, Langley suggested that
the receptive substances of the denervated rabbit muscle had degenerated in addition to the
nerve endings, which explained why Magnus had no longer obtained a contraction on
injection of physostigmine. Yet this argument constituted a certain contradiction to
Langley's earlier observation that denervated muscle cells actually showed an increased
sensitivity for drugs such as nicotine and adrenalin. On the other hand, Magnus had to admit
that curare might have two points of attack: the nerve ending and the muscle cell.89 By the
following year both researchers had collected more evidence to support their divergent points
of view. Magnus argued from experiments conducted by himself, by Langley's Cambridge
collaborator Hugh Kerr Anderson (1865±1928) and others that similar inconsistencies
resulted about the point of attack of atropine if one drew conclusions from its antagonistic
action to pilocarpine and physostigmine.90 Langley demonstrated different kinds of con-
traction after nicotine and after physostigmine had been applied to muscle, and concluded
from this that there had to be ``different receptive radicles'' for the two poisons.91 In this way,
Magnus' criticism led eventually to a greater complexity of Langley's receptor concept.
Langley also had to consider recent results of Hermann Fuhner (1871±1944) of the
Pharmacological Institute in W urzburg, who had studied the muscular effects of the
curare-like substance guanidine for his Habilitation thesis.92 Fuhner had found that
guanidine chloride failed to produce the usual contraction (``fibrillar twitching'') of the
frog's gastrocnemius when it was applied to the muscle eleven and thirteen days after its
nerve had been cut. For the W urzburg researcher this suggested an action of guanidine (and,
by extension, of curare) on nerve endings, which would have degenerated by that time. Yet,
he obtained some guanidine contractions again from the sixteenth and eighteenth day
onwards and explained this by proposing regeneration of the nerve endings.93 In Langley's
view, F uhner's hypotheses about degeneration and then regeneration in the absence of a
connection to the central nervous system were untenable. Moreover, Langley referred to
denervation experiments on another leg muscle, the sartorius, which showed with
histological staining that the nerve endings needed about six weeks to degenerate and
did not begin to regenerate until the sixty-ninth day. Accordingly he did not accept Fuhner's
evidence for guanidine's action on nerve endings rather than on muscle cells.94 Still, the
experiments of the W urzburg pharmacologist illustrated the uncertainties inherent in the
nerve-degeneration method, and in this way cast doubt over another element in Langley's
argument for the existence of receptive substances in cells.
Criticism came not only from German researchers but also from colleagues at home.
Stimulated by Langley's ideas on receptive substances and Ehrlich's on chemoreceptors,

88 92
R Magnus, `Kann man den Angriffspunkt eines H Fuhner, `Curarestudien. I. Die periphere
Giftes durch antagonistische Giftversuche Wirkung des Guanidins', Archiv f ur experimentelle
bestimmen?', Pfl uger's Archiv f
ur die gesamte Pathologie und Pharmakologie, 1907, 58: 1±49.
Physiologie, 1908, 123: 99±112, on p. 106. Guanidine produces fibrillar twitching followed by
89
Ibid., p.107. curare-like paralysis of the muscle.
90 93
Ibid., pp. 108±12. Ibid., pp. 35±9, 44, 48.
91 94
Langley, `On the contraction' (1908), note 86 Langley, `On the contraction' (1908), note 86
above, p. 299. above, pp. 298±9.

170
 John Newport Langley and a Receptor Theory of Drug Action
Walter Dixon, who had become a lecturer in pharmacology at Cambridge, published in 1909
a study of the specific action of strychnine on the spinal cord. Working with emulsions of
spinal cord, he and his collaborator in the Pharmacological Laboratory, Philip Hamill
(1883±1959), did not find any evidence for a chemical combination of the alkaloid with
the nervous tissue. They therefore questioned the existence of specific receptors for veget-
able alkaloids. Yet, based on another series of experiments, in which they examined the
effects of secretin on the pancreas, they proposed that there were receptor substances for the
body's own internal secretions. Poisons, they hypothesized, might act by liberating specific
hormones, which would then combine with hormone receptors.95 Doubts about Langley's
concept of receptive substances were also raised from a chemical point of view. George
Barger (1878±1939) and Henry Hallett Dale (1875±1968), then working at the Wellcome
Physiological Research Laboratories, showed that a wide range of structurally differing
amines apparently mimicked the physiological effects of sympathetic nerve stimulation.
However, they could not identify a common structural component that was specific for these
``sympathomimetic'' amines. On these grounds they were sceptical about Langley's
suggestion that drugs entered into chemical combinations with specific receptive side
chains of the cell.96
Perhaps the most lasting challenge to Langley's concept of receptive substances arose,
however, from a new theory of the mode of action of drugs, which was then developed by the
Freiburg pharmacologist Walther Straub (1874±1944). Inspired by studies of drug absorp-
tion, made by his academic mentor Rudolf Boehm (1844±1926) in Leipzig,97 the young
Straub extended this line of research during a stay at the Zoological Station in Naples in the
spring of 1905. His experimental model was the isolated heart of the marine snail, Aplysia,
on which he examined the effects of muscarine and its antagonist atropine. Muscarine
caused typically a slowing of the heartbeat. Straub concluded from his experiments that this
effect occurred only as long as the poison entered the heart cells. The effect did not depend,
in his view, on an action of muscarine within the cell itself. What was important was rather
the gradient in the poison's concentration between the outside and the inside of the cell
membrane, or the ``concentration potential'' as he called it, which kept the process of
absorption in motion. After the cells had become saturated with muscarine, a further
increase of its concentration outside the cell had no further effect. On this basis Straub
developed a ``potential poison theory'' (Potentialgifttheorie): while the poison was entering
the cell, the membrane was unable to excrete the cell's waste products. These accumulated
and damaged the cell, leading to cessation of its functions. In Straub's opinion, this theory
was applicable not only to muscarine but to other alkaloids as well, such as pilocarpine,
physostigmine and nicotine, and also to the hormone adrenalin. Moreover, the antagonism
between muscarine and atropine could be explained with the hypothesis that atropine
slowed the absorption of muscarine into the heart cells.98

95 97
W E Dixon and P Hamill, `The mode of action of R Boehm, `Einige Beobachtungen uber die
specific substances with special reference to secretin', Nervenendwirkung des Curarin', Archiv f ur
J. Physiol., 1909, 38: 314 ±36. See also Langley, `On experimentelle Pathologie und Pharmakologie, 1895,
the contraction' (1909), note 86 above, pp. 293± 4. 35: 16 ±22.
96 98
G Barger and H H Dale, `Chemical structure W Straub, `Zur Kinetik der Muskarinwirkung
and sympathomimetic action of amines', J. Physiol., und des Antagonismus Muskarin-Atropin', Pfl uger's
1910, 41: 19±59, on p. 56. Archiv f
ur die gesamte Physiologie, 1907, 119: 127±51.

171
 Andreas-Holger Maehle
This essentially physical theory of drug action stood in marked contrast to the concept of
specific chemical binding of drugs to receptive side chains as proposed by Langley and
(subsequently) Ehrlich. As Straub put it rather bluntly in his Freiburg inaugural lecture in
1908, any remarks on a direct relationship between the chemical structure and physiological
effect of a drug were mere speculation.99 Langley took Straub's observations seriously, but
provided an explanation for them that was in harmony with his chemical theory. As long as
the poison combined chemically with the receptive substances they ``set up a stimulus'' to
the cell. When they were saturated, there was no more stimulus and thus no further effect.
Similarly, the antagonism between atropine and muscarine could be explained with the
hypothesis that atropine combined with the receptive substances and in this way prevented
the effect of muscarine.100
Langley also used the similarities with Ehrlich's side chain theory to support his own
concept of receptive substances. He interpreted these as ``atom-groups of the protoplasm''
of the cell. Two such atom-groups had to be distinguished: the ``receptive'' and the ``funda-
mental''. When chemical substances bound to the receptive atom-groups, they would alter
the protoplasmic molecule of the cell and in this way change the cell's function. In less
differentiated cells these atom-groups could also split off from the cell and act as antibodies,
as suggested in Ehrlich's theory of immunity. In more differentiated cells, such as those of
the muscles and glands, the receptive atom-groups had undergone a ``special development'',
which enabled them to combine with hormones or with alkaloids. Due to those cells'
connection with nerve fibres these further developed atom-groups tended to concentrate
in the region of the nerve endings. The ``fundamental'' atom-groups, by contrast, were
essential for the cell's life. If a chemical substance bound to such a group, the cell would be
damaged and die. Langley pointed out that this latter type of atom-groups had been demon-
strated in Ehrlich's recent experiments with arsenic compounds on trypanosomes (i.e. the
protozoa causing sleeping sickness). If arsenic bound to the chemoreceptors of the trypano-
somes, these micro-organisms were destroyed.101
By making this distinction, Langley used, on the one hand, the side chain theory of
Ehrlich to bolster his own concept of receptive substances. In 1908 Ehrlich had been
awarded the Nobel Prize for his studies into immunity. As Langley put it, his hypothesis
of receptive substances constituted ``an extension of Ehrlich's side chain hypothesis''.102
On the other hand, Langley preserved the originality of his own research by making it clear
that Ehrlich's studies into drug binding were concerned with a different type of
receptor from the one that he had examined in his experiments with nicotine and curare.

99 
W Straub, Gift und Organismus. Offentliche 101
Ibid., pp. 294±5. On Ehrlich's chemotherapeutic
Antrittsrede, gehalten am 26. Februar 1908 in der experiments on trypanosomes, see Parascandola
Universitats-Aula, Freiburg i. Br. and Leipzig, and Jasensky, op. cit., note 2 above, pp. 216±20;
Speyer & Kaerner, 1908, pp. 11±13. On the early Silverstein, op. cit., note 3 above, pp. 130±1;
history of studies into the relationship between M Weatherall, In search of a cure: a history of
structure and effects of drugs, see W F Bynum, pharmaceutical discovery, Oxford University
`Chemical structure and pharmacological action: a Press, 1990, pp. 58±60.
102
chapter in the history of 19th century molecular Langley, `On the contraction' (1909), note 86
pharmacology', Bull. Hist. Med., 1970, 44: 518±38. above, p. 295.
100
Langley, `On the contraction' (1909), note 86
above, pp. 291±2.

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 John Newport Langley and a Receptor Theory of Drug Action
Langley emphasized that he had arrived at his own receptor concept ``by entirely different
experiments and by a different line of argument'' and that he had proposed the binding of
drugs to side chains at a time (1905/6) when Ehrlich had not yet considered this possibil-
ity.103 Significantly, Langley did not adopt the term ``receptor'', which Ehrlich had intro-
duced in 1900 in the context of his immunological research,104 nor Ehrlich's neologism
``chemoreceptors'' of 1907. He continued to employ his own term ``receptive substances''.
One of Langley's postgraduate students, the later Nobel Prize winner Archibald Vivian
Hill (1886±1977), provided in 1909 further evidence for his professor's essentially chemical
receptor theory and against the ``physical view''. Hill used a different approach to the
problem by performing a quantitative and mathematical analysis of the contractions pro-
duced by nicotine, and the relaxation caused by its antagonist curare, in the frog's rectus
abdominis muscle. He also examined these physiological effects at different temperatures.
The formulas at which he arrived led him to the firm conclusion that nicotine as well as
curare formed reversible, chemical combinations with a constituent of the muscle.105
Langley's predominantly qualitative evidence for the existence of receptive substances
in cells was thus endorsed by an analysis of quantitative data. Nevertheless, the physical
theory of drug action as introduced by Straub became a strong competitor of the ``chemical''
drug receptor theory, and remained so during the 1910s and 1920s.106 It was only after
Langley's death that the quantitative arguments for drug receptors were further developed
by the pharmacologist Alfred Joseph Clark (1885±1941).107 Langley himself, while
acknowledging further developments in a physical theory of the specific action of poisons
(for example, theories about differences in the permeability and solvent power of the cell
membrane), stayed committed to his concept of receptive substances and to a chemical
theory of drug effects.108 In his final synthesis of his research into the autonomic nervous
system, published in 1921, he declared:
The known physical characters of drugs are insufficient to account for the effects they produce,
though they account for a difference in rate of action; in consequence I consider that there is a
chemical combination between the drug and a constituent of the cellÐthe receptive substance. On
the theory of chemical combination it seems necessarily to follow that there are two broad classes
of receptive substances; those which give rise to contraction, and those which give rise to
inhibition.109

103
Ibid. Sciences, 1982, 3: 421±3; idem, op. cit., note 2 above,
104
See Prull, op. cit., note 4 above. pp. 148±53; D H Clark, Alfred Joseph Clark
105
A V Hill, `The mode of action of nicotine and 1885±1941. A memoir, Glastonbury, C & J Clark,
curare, determined by the form of the contraction 1985, pp. 13±22; Robinson, op. cit., note 1 above,
curve and the method of temperature coefficients', pp. 144±6; Maehle, Prull and Halliwell, op. cit,
J. Physiol., 1909, 39: 361±73. note 2 above, pp. 640±1.
106 108
For the continuing debates over a chemical J N Langley, `Note on the action of nicotine
versus a physical interpretation of drug action, see and curare on the receptive substance of the frog's
J Parascandola, `The controversy over structure- rectus abdominis muscle', J. Physiol., 1910, 40:
activity relationships in the early twentieth century', lviii±lix; idem, `The antagonism of curare and
Pharmacy in History, 1974, 16: no. 2, 54±63. nicotine in skeletal muscle', J. Physiol., 1914, 48:
107
See, in particular, A J Clark, The mode of 73±108, on p. 106; idem, `Persistence of the central
action of drugs on cells, London, Edward Arnold, somatic effect of strychnine after a large dose of
1933. For accounts of Clark's contribution to the nicotine', J. Physiol., 1918, 52: xliv±xlv.
109
development of the receptor theory, see J Parascandola, Idem, The autonomic nervous system, note 16
`A. J. Clark: quantitative pharmacology and the above, p. 44.
receptor theory', Trends in Pharmacological

173
 Andreas-Holger Maehle
Conclusions
This paper has illustrated the complexities that were involved in the conceptualization of
the drug receptor, one of the major ideas in twentieth-century biomedical science. Langley's
path to a receptor concept of pharmacological action was neither straightforward nor the
result of a specific research plan. His ideas about the interaction of drugs and poisons with
cells developed intermittently over a period of thirty years and in diverse research contexts.
The main contexts were the physiology of glandular secretion and of the autonomic nervous
system. In addition we can identify a number of subsidiary contexts, such as the emerging
theory of mutual antagonism of drugs, Ehrlich's side chain theory of immunity, early
hormone research, the beginnings of the neurone theory, and the first ideas about chemical
neurotransmission.
While our historical reconstruction allows us to recognize and follow the inner logic of
Langley's intellectual route to his concept of receptive substances, it also identifies the
various influences from other British and from German medical scientists upon his thought
and experimentation. In retrospect, Elliott's ideas about the action of adrenalin on the
``myoneural junction'' appear to have been especially relevant in Langley's final steps
towards his receptor concept. Those influences were also relevant, as some of the key
methods employed by Langley in proving the existence of receptive substances were
contested at the time. As we have seen, fundamental questions were raised about the validity
of antagonistic drug trials, and there were considerable uncertainties involved in the method
of nerve degeneration. The question whether antagonistic drugs such as nicotine and
curare, or pilocarpine and atropine, acted on nerve endings or directly on the effector
cells (muscle cells, gland cells etc.), remained undecided for many researchers despite
the experimental evidence provided by Langley.
These inherent methodological problems are an important clue for our understanding of
the difficulties in the recognition of the receptor concept. Another reason for these diffi-
culties was the direct competition between Langley's (and later Ehrlich's) chemical ideas
about drug binding and physical theories of drug action in the wake of Straub's influential
studies on the heart of Aplysia. Despite Hill's early quantitative evidence in favour of
Langley's receptive substances, the controversy over a chemical versus a physical effect of
drugs on cells remained unresolved beyond the time of Langley's death in 1925. Through
Clark's further quantitative analysis of pharmacological effects, given in his book of 1933,
The mode of action of drugs on cells, receptor theory was re-asserted and definitely put on
the map of theoretical pharmacology. But even then, it remained just that, a theory, until
receptor proteins began to be isolated from cell membranes in the 1970s. Langley's concept
of receptive substances was vindicated in this way, and since then, receptors have become
objects of extensive scientific exploration and manipulation.

174