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“Receptive Substances”: John Newport Langley (1852–1925) and his Path to a Receptor Theory of Drug Action

Published online by Cambridge University Press:  07 December 2011

Andreas-Holger Maehle
Andreas-Holger Maehle
Affiliation:
Centre for the History of Medicine and Disease, Wolfson Research Institute, University of Durham, Queen's Campus, University Boulevard, Stockton-on-Tees TS17 6BH, United Kingdom
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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 cornerstone 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 pharmaceuticals—especially the beta-adrenergic receptor antagonist propranolol (introduced in 1965)—promoted 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.

Type
Articles
Information
Medical History , Volume 48 , Issue 2 , 01 April 2004 , pp. 153 - 174
Copyright
Copyright © Cambridge University Press 2004

References

1 R G Shanks, ‘The discovery of beta adrenoceptor blocking drugs’, in M J Parnham and J Bruinvels (eds), Discoveries in pharmacology, Amsterdam, Elsevier, 1983–86, vol. 2, pp. 37–72; P G Waser, ‘The cholinergic receptor’, ibid., vol. 3, pp. 157–202; S E Cozzens, Social control and multiple discovery in science: the opiate receptor case, Albany, State University of New York Press, 1989; J D Robinson, Mechanisms of synaptic transmission: bridging the gaps (1890–1990), Oxford University Press, 2001, pp. 143–70, 199–218. On the history of research into neurotransmission, see also J-C Dupont, Histoire de la neurotransmission, Paris, Presses Universitaires de France, 1999.

2 J Parascandola and R Jasensky, ‘Origins of the receptor theory of drug action’, Bull. Hist. Med., 1974, 48: 199–220; J Parascandola, ‘The development of receptor theory’, in Parnham and Bruinvels, op. cit., note 1 above, vol. 3, pp. 129–56. See also A-H Maehle, C-R Prüll and R F Halliwell, ‘The emergence of the drug receptor theory’, Nature Reviews Drug Discovery, 2002, 1: 637–41.

3 A M Silverstein, Paul Ehrlich's receptor immunology: the magnificent obsession, San Diego, Academic Press, 2002.

4 C-R Prüll, ‘Part of a scientific master plan? Paul Ehrlich and the origins of his receptor concept’, Med. Hist., 2003, 47: 332–56.

5 See Parascandola and Jasensky, op. cit., note 2 above, pp. 200–1, 211–6; M R Bennett, ‘The concept of transmitter receptors: 100 years on’, Neuropharmacology, 2000, 39: 523–46.

6 G L Geison, Michael Foster and the Cambridge School of Physiology: the scientific enterprise in late Victorian society, Princeton University Press, 1978, pp. 236–44, 313–27. Langley is mentioned in passing in M Weatherall, Gentlemen, scientists and doctors: medicine at Cambridge, 1800–1940, Woodbridge, Boydell Press, 2000.

7 The biographical details of this section have been taken from: ‘Langley, John Newport’, entry no. 3949 in Register, St John's College, Cambridge; W M Fletcher, ‘John Newport Langley: in memoriam’, J. Physiol., 1926, 61: 1–27; idem, ‘John Newport Langley—1852–1925’, Proc. R. Soc. Lond., series B, 1927, 101: xxxiii–xli; R du Bois-Reymond, ‘John Newport Langley zum Gedächtnis’, Ergebisse der Physiologie, 1926, 25: xv–xix; C S Sherrington, ‘Langley, John Newport’, in J R H Weaver (ed.), Dictionary of National Biography 1922–1930, Oxford University Press, 1937, pp. 478–81; G L Geison, ‘Langley, John Newport’, in C C Gillispie (ed.), Dictionary of Scientific Biography, New York, Charles Scribner's Sons, 1973, vol. 8, pp. 14–19.

8 J N Langley, ‘Preliminary notice of experiments on the physiological action of jaborandi’, Br. med. J., 1875, i: 241–2; idem, ‘On the physiological action of jaborandi’, Proc. Cambr. Phil. Soc., 1875, April, pp. 402–4; idem, ‘The action of jaborandi on the heart’, J. Anat. Physiol., 1875, 10: 187–201.

9Idem, ‘The action of pilocarpin on the sub-maxillary gland of the dog’, J. Anat. Physiol., 1876, 11: 173–80; idem, ‘On the physiology of the salivary secretion. Part II. On the mutual antagonism of atropin and pilocarpin, having especial reference to their relations in the sub-maxillary gland of the cat’, J. Physiol., 1878, 1: 339–69.

10 The Cruelty to Animals Act, 1876, clauses 3 and 5. On the history and debate of this piece of legislation, see R French, Antivivisection and medical science in Victorian society, Princeton University Press, 1975; N A Rupke (ed.), Vivisection in historical perspective, London, Routledge, 1990.

11 For example, Langley, ‘The action of pilocarpin’, note 9 above, p. 174 (with reference to experiments on dogs): “In every case the animal was placed under anaesthetics during the operation and killed at its close; the anaesthetics employed have been various, most frequently morphia or chloroform, occasionally chloral hydrate, or croton chloral hydrate.”

12 For a summary account, see idem, ‘The salivary glands’, in E A Schäfer (ed.), Text-book of physiology, Edinburgh, Pentland, 1898–1900, vol. 1, pp. 475–530.

13 E Klein, J N Langley and E A Schäfer, ‘On the cortical areas removed from the brain of a dog, and from the brain of a monkey’, J. Physiol., 1883, 4: 231–47; J N Langley, ‘The structure of the dog's brain’, J. Physiol., 1883, 4: 248–85; idem, ‘Report on the parts destroyed on the right side of the brain of the dog operated on by Prof. Goltz’, J. Physiol., 1883, 4: 286–309; J N Langley and C S Sherrington, ‘Secondary degeneration of nerve tracts following removal of the cortex of the cerebrum in the dog’, J. Physiol., 1884, 5: 49–65; J N Langley and A S Grünbaum, ‘On the degeneration resulting from removal of the cerebral cortex and corpora striata in the dog’, J. Physiol., 1890, 11: 606–28. For the general context of this research, see E Clarke and L S Jacyna, Nineteenth-century origins of neuroscientific concepts, Berkeley, University of California Press, 1987.

14 Cf. Geison, op. cit., note 6 above, pp. 313–19; J N Langley, ‘Walter Holbrook Gaskell, 1847–1914’, Proc. R. Soc. Lond., series B, 1915, 88: xxvii–xxxvi. On the history of research into the vegetative nervous system prior to Gaskell and Langley, see Clarke and Jacyna, op. cit., note 13 above, pp. 308–70; and for a brief summary account, E H Ackerknecht, ‘The history of the discovery of the vegetative (autonomic) nervous system’, Med. Hist., 1974, 18: 1–8.

15 J N Langley and W L Dickinson, ‘On the local paralysis of peripheral ganglia, and on the connexion of different classes of nerve fibres with them’, Proc. R. Soc. Lond., 1889, 46: 423–31.

16 For summary accounts, see J N Langley, ‘Presidential address, Section I—Physiology’, Report of British Association for 1899, pp. 881–92 (on the nomenclature, p. 883); idem, ‘The sympathetic and other related systems of nerves’, in Schäfer (ed.), op. cit., note 12 above, vol. 2, pp. 616–96; J N Langley, ‘The autonomic nervous system. Presidential address’, Brain, 1903, 26: part I, 1–26; idem, ‘The nomenclature of the sympathetic and of the related systems of nerves’, Zentralblatt für Physiologie, 1913, 27: 149–52; idem, The autonomic nervous system, part I, Cambridge, W Heffer & Sons, 1921 (no second part of this monograph appeared).

17Idem, ‘Das sympathische und verwandte nervöse Systeme der Wirbeltiere (autonomes nervöses System)’, Ergebnisse der Physiologie, 1903, 2: part 2, 818–72; idem, ‘The autonomic nerves’, Nederlandsch Tijdschrift voor Geneeskunde, 1905, no. 16, pp. 1013–30.

18 Cf. the obituary on Langley by W M Fletcher in the Journal of Physiology, note 7 above, pp. 12–13.

19 J N Langley, ‘On the reaction of cells and of nerve-endings to certain poisons, chiefly as regards the reaction of striated muscle to nicotine and to curari’, J. Physiol., 1905, 33: 374–413. For a detailed discussion of this paper, see below.

20 On Langley's engagement for the new building, which was funded by a donation from the Drapers' Company, see University of Cambridge, Department of Manuscripts and University Archives, ‘The Professor of Physiology 1878 to 1925’, UA CUR 39.37, pp. 17, 31, and Department of Physiology, ‘History of Lab Building 1912–14 … Papers in connection with building of Physiol. Lab. Box II’.

21 J N Langley and T Kato, ‘The rate of loss of weight in skeletal muscle after nerve section with some observations on the effect of stimulation and other treatment’, J. Physiol., 1915, 49: 432–40; J N Langley and M Hashimoto, ‘On the suture of separate nerve bundles in a nerve trunk and on internal nerve plexuses’, J. Physiol., 1917, 51: 318–45; J N Langley, ‘On the separate suture of nerves in nerve trunks’, Br. med. J., 1918, i: 45–7; J N Langley and M Hashimoto, ‘Observations on the atrophy of denervated muscle’, J. Physiol., 1918, 52: 15–69.

22 Fletcher, ‘John Newport Langley: in memoriam’, note 7 above, pp. 14–15.

23 See Geison, op. cit., note 6 above, pp. 193–235, 242–4.

24 Langley, ‘Preliminary notice’, note 8 above, p. 242.

25 This view on the mode of action of curare went back to experiments by Claude Bernard in the 1840s and 1850s. See J M D Olmsted, Claude Bernard, physiologist, London, Cassell, 1939, pp. 223–8.

26 Langley, ‘On the physiological action of 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.

28 Ibid., p. 190.

29 Langley, ‘Preliminary notice’, note 8 above, p. 242; idem, ‘On the physiological action of jaborandi’, note 8 above, pp. 403–4.

30Idem, ‘The action of jaborandi on the heart’, note 8 above, pp. 194–5.

31 Cf. ibid., pp. 197–8.

32 Geison, op. cit., note 6 above, p. 242.

33 Langley, ‘The action of jaborandi on the heart’, note 8 above, p. 198.

34 Pilocarpine was isolated by A W Gerrard of University College Hospital, London; see ‘The alkaloid of jaborandi’, Chemist and Druggist, 1875, June 15, p. 192.

35 See, for example, experiments with jaborandi on the sub-maxillary gland of the dog described in ‘Vulpian on the action of jaborandi and atropia on perspiration’, London Medical Record, 1875, March 3, p. 132; and Langley, ‘Preliminary notice’, note 8 above, p. 242.

36 Langley, ‘The action of pilocarpin’, note 9 above, p. 180.

37 B Luchsinger, ‘Die Wirkungen von Pilocarpin und Atropin auf die Schweissdrüsen der Katze. Ein Beitrag zur Lehre vom doppelseitigen Antagonismus zweier Gifte’, Pflüger's Archiv für Anatomie und Physiologie, 1877, 15: 482–92, on p. 488. Quotation in Langley's translation, cf. Langley, ‘On the physiology of the salivary secretion’, note 9 above, p. 339.

38 Luchsinger, op. cit., note 37 above, pp. 488, 491–2.

39 Langley, ‘On the physiology of the salivary secretion’, note 9 above, p. 367.

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.

42 M J Rossbach, ‘Neue Studien über den physiologischen Antagonismus der Gifte’, Pflüger's Archiv für Anatomie und Physiologie, 1879, 21: 1–38, on pp. 33–8.

43 J N Langley, ‘On the antagonism of poisons’, J. Physiol., 1880, 3: 11–21.

44 Ibid., p. 19.

45 Langley and Dickinson, op. cit., note 15 above. See also J N Langley and W L Dickinson, ‘On the progressive paralysis of the different classes of nerve cells in the superior cervical ganglion’, Proc. R. Soc. Lond., 1890, 47: 379–90; J N Langley and H K Anderson, ‘The action of nicotine on the ciliary ganglion and on the endings of the third cranial nerve’, J. Physiol., 1892, 13: 460–8.

46 J N Langley and W L Dickinson, ‘Pituri and nicotin’, J. Physiol., 1890, 11: 265–306.

47 J N Langley and W L Dickinson, ‘Action of various poisons upon nerve-fibres and peripheral nerve-cells’, J. Physiol., 1890, 11: 501–27. On the tradition of physiological experimentation with alkaloids, going back to the work of François Magendie, see J E Lesch, Science and medicine in France: the emergence of experimental physiology, 1790–1855, Cambridge, MA, Harvard University Press, 1984.

48 For a recent summary of the origins of the discontinuity or neurone theory, see Robinson, op. cit., note 1 above, pp. 1–30.

49 J N Langley, ‘On the stimulation and paralysis of nerve-cells and of nerve-endings. Part I’, J. Physiol., 1901, 27: 224–36, on p. 224.

50 Ibid., p. 229.

51 Cf. ibid., pp. 224–5.

52 G Oliver and E A Schäfer, ‘The physiological effects of extracts of the suprarenal capsules’, J. Physiol., 1895, 18: 230–76, on pp. 239, 245–7.

53 M Lewandowsky, ‘Ueber die Wirkung des Nebennierenextractes auf die glatten Muskeln, im Besonderen des Auges’, Pflüger's Archiv für Anatomie und Physiologie, 1899, pp. 360–6.

54 H Boruttau, ‘Erfahrungen über die Nebennieren’, Archiv für die gesamte Physiologie, 1899, 78: 97–128, on pp. 109–11.

55 J N Langley, ‘Observations on the physiological action of extracts of the supra-renal bodies’, J. Physiol., 1901, 27: 237–56, on pp. 244–5.

56 Ibid., pp. 241–2.

57 Ibid., p. 256. This observation places Langley also in the history of the discovery of chemical neurotransmission. In 1946 Ulf Svante von Euler provided persuasive evidence that noradrenaline was the transmitter substance of sympathetic nerves. See Robinson, op. cit., note 1 above, pp. 56, 123–4; Dupont, op. cit., note 1 above, pp. 46, 173–4.

58 J N Langley, ‘The autonomic nervous system. Presidential address’, note 16 above, pp. 6–7.

59 T R Elliott, ‘The action of adrenalin’, J. Physiol., 1905, 32: 401–67, on p. 402. On the identification of the active principle of the suprarenal glands, see E M Tansey, ‘What's in a name? Henry Dale and adrenaline, 1906’, Med. Hist., 1995, 39: 459–76, on pp. 465–6, 472–3.

60 T R Elliott, ‘On the action of adrenalin’, J. Physiol., 1904, 31: xx–xxi, on p. xxi.

61 See Robinson, op. cit., note 1 above, pp. 56–9; Bennett, op. cit., note 5 above, pp. 530–1; Dupont, op. cit., note 1 above, p. 47.

62 T G Brodie and W E Dixon, ‘Contributions to the physiology of the lungs. Part II. On the innervation of the pulmonary blood vessels; and some observations on the action of suprarenal extract’, J. Physiol., 1904, 30: 476–502, on pp. 500–1.

63 Elliott, op. cit., note 59 above, pp. 431–2.

64 Brodie and Dixon, op. cit., note 62 above, pp. 497–8.

65 Elliott, op. cit., note 59 above, pp. 434–7.

66 Ibid., p. 437–8. On the history of the identification of acetylcholine as the transmitter in these other synapses, see Robinson, op. cit., note 1 above, pp. 55–68, 70–6; Dupont, op. cit, note 1 above; E M Tansey, ‘Sir Henry Dale and autopharmacology: the role of acetylcholine in neurotransmission’, in C Debru (ed.), Essays in the history of the physiological sciences, Amsterdam, Rodopi, 1995, pp. 179–93.

67 Elliott acknowledged his “indebtedness for advice” to Langley, but also to Gaskell and H K Anderson. Elliott, op. cit., note 59 above, p. 467.

68 Langley, op. cit., note 19 above, pp. 374–80. On the preparation of the tabloid extract, idem, op. cit., note 55 above, p. 237.

69Idem, op. cit., note 19 above, pp. 375–6.

70 Ibid., pp. 380–93.

71 Ibid., pp. 393–9.

72 Ibid., p. 399.

73 Ibid., pp. 399–400.

74 Ibid., p. 400.

75 Ibid., p. 411.

76 See Parascandola and Jasensky, op. cit., note 2 above, pp. 205–10. For a full discussion of Ehrlich's side chain theory of antibody formation, see Silverstein, op. cit., note 3 above, pp. 77–94.

77 J N Langley, ‘Croonian Lecture, 1906.—On nerve endings and on special excitable substances in cells’, Proc. R. Soc. Lond., series B, 1906, 78: 170–94, on p. 181.

78 Parascandola and Jasensky, op. cit., note 2 above, pp. 210–11.

79 Langley, op. cit., note 19 above, p. 412.

80 Ibid.

81 Ibid., pp. 405–10, 413. See also Langley, op. cit., note 77 above, p. 193.

82 T R Elliott, ‘The innervation of the bladder and urethra’, J. Physiol., 1907, 35: 367–445, on p. 442.

83 Cf. H H Dale, ‘Thomas Renton Elliott 1877–1961’, Biographical Memoirs of Fellows of the Royal Society, 1961, 7: 53–74, on pp. 65–6.

84 Langley, op. cit., note 77 above, pp. 185–8.

85Idem, ‘Über Nervenendigungen und spezielle rezeptive Substanzen in Zellen’, Zentralblatt für Physiologie, 1906, 20: 290–1.

86Idem, ‘Nouvelles observations sur la nature non-spécifique des terminaisons nerveuses motrices et sur l'existence de radicules «réceptives» dans le muscle’, Archives Internationales de Physiologie, 1907, 5 : 115–8. A full account of the experiments underlying Langley's theory of two kinds of nicotine receptors is given in idem, ‘On the contraction of muscle, chiefly in relation to the presence of “receptive” substances’, J. Physiol., 1907, 36: 347–84; 1908, 37: 165–212; 285–300; 1909, 39: 235–95.

87 In 1908 Magnus became professor in Utrecht, where he founded the first pharmacological institute of the Netherlands. See O Magnus, Rudolf Magnus, physiologist and pharmacologist, 1873–1927, ed. L M Schoonhoven, Amsterdam, Koninklijke Nederlandse Akademie van Wetenschappen, and Dordrecht, Kluwer Academic Publishers, 2002. Magnus' joint work with Langley in the Cambridge Physiological Laboratory was published as: J N Langley and R Magnus, ‘Some observations of the movements of the intestine before and after degenerative section of the mesenteric nerves’, J. Physiol., 1905, 33: 34–51.

88 R Magnus, ‘Kann man den Angriffspunkt eines Giftes durch antagonistische Giftversuche bestimmen?’, Pflüger's Archiv für die gesamte Physiologie, 1908, 123: 99–112, on p. 106.

89 Ibid., p.107.

90 Ibid., pp. 108–12.

91 Langley, ‘On the contraction’ (1908), note 86 above, p. 299.

92 H Fühner, ‘Curarestudien. I. Die periphere Wirkung des Guanidins’, Archiv für experimentelle Pathologie und Pharmakologie, 1907, 58: 1–49. Guanidine produces fibrillar twitching followed by curare-like paralysis of the muscle.

93 Ibid., pp. 35–9, 44, 48.

94 Langley, ‘On the contraction’ (1908), note 86 above, pp. 298–9.

95 W E Dixon and P Hamill, ‘The mode of action of specific substances with special reference to secretin’, J. Physiol., 1909, 38: 314–36. See also Langley, ‘On the contraction’ (1909), note 86 above, pp. 293–4.

96 G Barger and H H Dale, ‘Chemical structure and sympathomimetic action of amines’, J. Physiol., 1910, 41: 19–59, on p. 56.

97 R Boehm, ‘Einige Beobachtungen über die Nervenendwirkung des Curarin’, Archiv für experimentelle Pathologie und Pharmakologie, 1895, 35: 16–22.

98 W Straub, ‘Zur Kinetik der Muskarinwirkung und des Antagonismus Muskarin-Atropin’, Pflüger's Archiv für die gesamte Physiologie, 1907, 119: 127–51.

99 W Straub, Gift und Organismus. Öffentliche Antrittsrede, gehalten am 26. Februar 1908 in der Universitäts-Aula, Freiburg i. Br. and Leipzig, Speyer & Kaerner, 1908, pp. 11–13. On the early history of studies into the relationship between structure and effects of drugs, see W F Bynum, ‘Chemical structure and pharmacological action: a chapter in the history of 19th century molecular pharmacology’, Bull. Hist. Med., 1970, 44: 518–38.

100 Langley, ‘On the contraction’ (1909), note 86 above, pp. 291–2.

101 Ibid., pp. 294–5. On Ehrlich's chemotherapeutic experiments on trypanosomes, see Parascandola and Jasensky, op. cit., note 2 above, pp. 216–20; Silverstein, op. cit., note 3 above, pp. 130–1; M Weatherall, In search of a cure: a history of pharmaceutical discovery, Oxford University Press, 1990, pp. 58–60.

102 Langley, ‘On the contraction’ (1909), note 86 above, p. 295.

103 Ibid.

104 See Prüll, op. cit., note 4 above.

105 A V Hill, ‘The mode of action of nicotine and curare, determined by the form of the contraction curve and the method of temperature coefficients’, J. Physiol., 1909, 39: 361–73.

106 For the continuing debates over a chemical versus a physical interpretation of drug action, see J Parascandola, ‘The controversy over structure-activity relationships in the early twentieth century’, Pharmacy in History, 1974, 16: no. 2, 54–63.

107 See, in particular, A J Clark, The mode of action of drugs on cells, London, Edward Arnold, 1933. For accounts of Clark's contribution to the development of the receptor theory, see J Parascandola, ‘A. J. Clark: quantitative pharmacology and the receptor theory’, Trends in Pharmacological Sciences, 1982, 3: 421–3; idem, op. cit., note 2 above, pp. 148–53; D H Clark, Alfred Joseph Clark 1885–1941. A memoir, Glastonbury, C & J Clark, 1985, pp. 13–22; Robinson, op. cit., note 1 above, pp. 144–6; Maehle, Prüll and Halliwell, op. cit, note 2 above, pp. 640–1.

108 J N Langley, ‘Note on the action of nicotine and curare on the receptive substance of the frog's rectus abdominis muscle’, J. Physiol., 1910, 40: lviii–lix; idem, ‘The antagonism of curare and nicotine in skeletal muscle’, J. Physiol., 1914, 48: 73–108, on p. 106; idem, ‘Persistence of the central somatic effect of strychnine after a large dose of nicotine’, J. Physiol., 1918, 52: xliv–xlv.

109Idem, The autonomic nervous system, note 16 above, p. 44.