Putting theory into practice: James Black, receptor theory and the development of the beta-blockers at ICI, 1958-1978

Medical History

Volumn 50, Issue 1, 2006, Pages 69-92

  Quirke, Viviane ^a  

^a OXFORD BROOKES UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BETA ADRENERGIC RECEPTOR BLOCKING AGENT; DRUG RECEPTOR;

ARTICLE; DRUG DESIGN; DRUG INDUSTRY; HISTORY; UNITED KINGDOM;

ADRENERGIC BETA-ANTAGONISTS; DRUG DESIGN; DRUG INDUSTRY; ENGLAND; HISTORY, 20TH CENTURY; RECEPTORS, DRUG;

EID: 33744758336     PISSN: 00257273     EISSN: None     Source Type: Journal    
DOI: 10.1017/S0025727300009455     Document Type: Review

References (226)

1. See J Parascandola, Origins of receptor theory', Trends Pharmacol. Sci., 1980, 1: 189-92;
2. idem, 'The development of receptor theory', in M J Parnham and J Bruinvels (eds), Discoveries in pharmacology, vol. 3, Pharmacological methods, receptors and chemotherapy, Amsterdam, Elsevier, 1986, pp. 129-56.
3. On the development of the receptor concept by Paul Ehrlich, see C-R Prüll, 'Part of a scientific master plan? Paul Ehrlich and the origins of his receptor concept', Med. Hist., 2003, 47: 332-56;
4. on John Langley's role in the elaboration of receptor theory, see A-H Maehle, '"Receptive substances": John Newport Langley (1852-1925) and his path to a receptor theory of drug action', Med. Hist., 2004, 48: 153-74.
5. A-H Maehle, C-R Prüll and R F Halliwell, 'The emergence of the drug receptor theory'. Nature Reviews, Aug. 2002, 1: 637-41, on p. 641.
6. See also C-R Prüll, A-H Maehle, and R F Halliwell, 'Drugs and cells-pioneering the concept of receptors', Pharmacy in History; 2003, 45: 18-30.
7. See the time line in Maehle, et al., Pharmacy in History; op. cit., note 2 above, p. 638.
8. On Black, see V P Gerskowitch, R A D Hull, and N P Shankley, 'The "pharmacological toolmaker's" rational approach to drug design: an appreciation of Sir James Black', Trends Pharmacol. Sci., 1988, 9: 435-7.
9. See also V Quirke, 'Black, James Whyte', Encyclopedia of life sciences, 20 vols, London, Nature Publications Group, 2002, vol. 3, pp. 300-1.
10. J W Black, 'Ahlquist and the development of beta-adrenoceptor antagonists', Postgrad, med. J., 1976, 52, Suppl. 4:
11. B I Hoffbrand, R G Shanks, and I Brick (eds), Ten years of propranolol: a symposium on the history and future of beta-blockade, (Amsterdam, 26-28 Sept. 1975): 11-13, on p. 11.
12. C Kennedy, ICI: the company that changed our lives, London, Hutchinson, 1986, pp. 136-41.
13. For a more detailed analysis of the origins of ICI's cardiovascular research programme, see V Quirke, 'From evidence to market: Alfred Spinks' 1953 survey of new fields for pharmacological research, and the origins of ICI's cardiovascular programme', in V Berridge and K Loughlin (eds), Medicine, the market, and the mass media: producing health in the twentieth century, London, Routledge, 2005, pp. 144-69.
14. W J Reader, Imperial Chemical Industries: a history, 2 vols, London, Oxford University Press, 1975, vol. 2, pp. 3, 13.
15. See J Lesch, 'Chemistry and biomedicine in an industrial setting: the invention of the sulfa drugs', in S H Mauskopf (ed.), Chemical sciences in the modern world, Philadelphia, University of Pennsylvania Press, 1993, pp. 158-215.
16. D Bovet, Une Chimie qui guérit: histoire de la découverte des sulfamides, Paris, Payot, 1988.
17. Kennedy, Une Chimie Qui Guérit: Histoire de la Découverte des Sulfamides, op. cit., note 6 above, pp. 120-1.
18. K Holland, 'IC Pharmaceutical', Pharmaceutical Journal, Sept. 1987, 12: 286-8.
19. See also C W Suckling and B W Langley, 'Francis Leslie Rose, 1909-1988', Bio. Mem. F.R.S., 1990, 36: 491-524, on p. 498.
20. Reader, Bio. Mem. F.R.S., op. cit., note 8 above, vol. 2, p. 286.
21. Reader, Bio. Mem. F.R.S., op. cit., Ibid.
22. Kennedy, Bio. Mem. F.R.S., op. cit., note 6 above, pp. 127-9.
23. Holland, Bio. Mem. F.R.S., op. cit., note 12 above, vol. 2, p. 286.
24. Reader, Bio. Mem. F.R.S., op. cit., note 8 above, vol. 2, p. 459;
25. Kennedy, Bio. Mem. F.R.S., op. cit., note 6 above, p. 129.
26. J A Woodbridge, 'Social aspects of pharmaceutical innovation: heart disease', PhD thesis, University of Aston, Birmingham, 1981, p. 26.
27. AstraZeneca ICI research report (hereafter ICI) CPR 3: minutes of 2nd meeting of the Chemotherapeutic Research Committee, 31 March 1948. ICI records are held at Alderley Park, Cheshire.
28. CPR 3: minutes of 2nd meeting of the Chemotherapeutic Research Committee, Ibid., minutes of meeting, 24 Sept. 1951.
29. CPR 3: minutes of 2nd meeting of the Chemotherapeutic Research Committee, Ibid., minutes of 1st meeting, 19 Jan. 1948. A member of the committee, Dr J Madinaveitia, for example, drew the Committee's attention to the "importance of biochemical work as a basis for new ideas and new lines of synthetic work". However, pharmacology rather than biochemistry was to provide ICI with their first angle of approach to the problem of hypertension.
30. CPR 3: minutes of 2nd meeting of the Chemotherapeutic Research Committee, Ibid., minutes of meeting, 19 July 1951.
31. The term "diseases of organic dysfunction", rather than the now more familiar "chronic diseases", was used at ICI to distinguish their study from that of infectious diseases. ICI CPR 33: Research Department, Biological Group (Diseases of Organic Dysfunction) Report, Oct.-Dec. 1954.
32. ICI CPR 3: 31 March 1953;
33. ICI CPR 8: 1 Dec. 1954;
34. ICI CPR 11: joint plan for 1954.
35. On Raventos, see D G Davey, 'Dr James Raventos', obituary, Br. J. Pharmacol., 1983, 80: 3.
36. A W Johnson, F L Rose and C W Suckling, 'Alfred Spinks, 1917-1982', Bio. Mem. F.R.S., 1984, 30: 567-94.
37. ICI CPR 35: Research Report of the Biological Group (Pharmacological Section) for July-Dec. 1955.
38. J M Thorp, 'An experimental approach to the problem of disordered lipid metabolism', J. Atheroscler. Res., 1963, 3: 351-60.
39. Johnson, et al., J. Atheroscler. Res., op. cit., note 25 above, p. 584.
40. R Vos, Drugs looking for diseases: innovative drug research and the development of the beta-blockers and the calcium antagonists, Dordrecht, Kluwer Academic, 1991, pp. 81-2. This comment is based on an interview with Black.
41. ICI CPR 50, 50/3: Research Department Period Report, 22 Jan. 1959.
42. Prüll, ICI CPR, op. cit., note 1 above;
43. also Maehle, ICI CPR, op. cit., note 1 above.
44. Parascandola, 'The development of receptor theory', ICI CPR, op. cit., note 1 above, pp. 150-3;
45. idem, 'A J Clark: quantitative pharmacology and the receptor theory'. Trends Pharmacol Sci., 1982, 3: 421-3.
46. On Clark, see also Prüll, et al., Trends Pharmacol Sci., op. cit., note 2 above, pp. 26-7.
47. For an indirect view of the development and gradual acceptance of receptor theory, see A Albert's series of textbooks on Selective toxicity. It is interesting to note that it was not until Albert became more confident in the scientific basis of receptor theory, in the 3rd edition of the series published in 1965, that he began to appreciate the role played by Clark. A Albert, Selective toxicity, 3rd ed., London, Methuen, 1965, pp. 45-7.
48. On Clark's life and scientific career, see E V Vemey and I Barcroft, 'Alfred Joseph Clark, 1885-1941', Obit. Not. F.R.S, 1939-41, 3: 969-84.
49. Parascandola, 'The development of receptor theory', Obit. Not. F.R.S, op. cit., note 1 above, pp. 149-50.
50. A J Clark and J Raventos, 'The antagonism of acetylcholine and of quaternary ammonium salts', Q. J. Exp. Phys., 1937, 26: 375-92.
51. See also Verney and Barcroft, Q. J. Exp. Phys., op. cit., note 32 above, p. 974.
52. Parascandola, 'J Clark', Q. J. Exp. Phys., op. cit., note 31 above, p. 422.
53. Clark is quoted in Prüll, et al., Q. J. Exp. Phys., op. cit., note 2 above, p. 27.
54. Parascandola, 'The development of receptor theory', Q. J. Exp. Phys., op. cit., note 1 above, p. 151;
55. idem, 'A J Clark', op. cit., note 31 above, p. 422.
56. E J Ariëns, 'Affinity and intrinsic activity in the theory of competitive inhibition', Arch. Int. Pharma. Thé., 1954, 99: 32-49;
57. R P Stephenson, 'A modification of receptor theory', Brit. J. Pharmacol Chemother., 1956, 11: 379-93.
58. Woodbridge, Brit. J. Pharmacol Chemother., op. cit., note 18 above, p. 137.
59. Woodbridge, Brit. J. Pharmacol Chemother., op. cit., Ibid., pp. 127, 135-6.
60. See also A Albert, Selective toxicity, 5th ed., London, Methuen, 1973, p. 220.
61. Prüll, et al., Selective Toxicity, 5th Ed., op. cit., note 2 above, p. 27.
62. Woodbridge, Selective Toxicity, 5th Ed., op. cit., note 18 above, p. 115.
63. Maehle, Selective Toxicity, 5th Ed., op. cit., note 1 above, p. 173.
64. 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.
65. H H Dale, 'On some physiological actions of ergot', J. Physiol., 1906, 34: 163-206.
66. See W F Bynum, An early history of the British Pharmacological Society, 1931-1981, London, British Pharmacological Society, 1981, pp. 8-9. By the time of the Second World War, Dale's leadership in science administration meant that he was himself no longer closely involved in scientific research.
67. Maehle, An Early History of the British Pharmacological Society, 1931-1981, op. cit., note 1 above, p. 171.
68. See also a later article by Dale on 'Pharmacology and nerve-endings', Proc. R. S. Med., 1935, 28: 319-32, on p. 319.
69. Woodbridge, Proc. R. S. Med., op. cit., note 18 above, p. 115.
70. G Barger and H H Dale, 'Chemical structure and sympathomimetic action of amines', J. Physiol., 1910-1911, 41: 19-59.
71. R P Ahlquist, 'A study of the adrenotropic receptors', Am. J. Phys., 1948, 153: 586-600;
72. Idem, 'Adrenergic receptors: a personal and practical view', Perspect. Biol. Med., 1973, 17: 119-22.
73. Vos, Perspect. Biol. Med., op. cit., note 28 above, pp. 71-2.
74. Ahlquist, 'Adrenergic receptors', Perspect. Biol. Med., op. cit., note 50 above, p. 120.
75. Vos, Perspect. Biol. Med., op. cit., note 28 above, pp. 72, 76.
76. Kennedy, Perspect. Biol. Med., op. cit., note 6 above, p. 137.
77. Vos, Perspect. Biol. Med., op. cit., note 28 above, p. 75.
78. Also G O Carrier, 'Evolution of the dual adrenergic receptor concept: key to past mysteries and modern therapy', in Parnham and Bruinvels (eds), Perspect. Biol. Med., op. cit., note 1 above, pp. 203-21, on pp. 217-18.
79. See Black, Perspect. Biol. Med., op. cit., note 5 above, p. 12.
80. Black, Perspect. Biol. Med., op. cit., Ibid.
81. U S von Euler, 'A specific sympathomimetic ergone in adrenergic nerve fibres (sympathin) and its relations to adrenaline and nor-adrenaline', Acta. Physiol. Scand., 1946, 12: 73-97;
82. A M Lands, 'The pharmacological activity of epinephrine and related dihydroxyphenylalkylamines', Pharmacol. Rev., 1949, 1: 279-309, on p. 301.
83. Black, Pharmacol. Rev., op. cit., note 5 above, p. 12.
84. See R A Maxwell and S B Eckhardt, Drug discovery: a casebook and analysis, Clifton, NJ, Humana Press, 1990, p. 13.
85. Also A M Barrett, 'Design of β-blocking drugs', in E J Ariëns (ed.), Drug design, New York, Academic Press, 1972, vol. 3, pp. 205-28, on p. 208;
86. R G Shanks, 'The discovery of beta adrenoceptor blocking drugs', in M J Parnham and J Bruinvels (eds), Discoveries in pharmacology, vol. 2, Haemodynamics, hormones and inflammation, Amsterdam, Elsevier, 1984, pp. 38-72.
87. C E Powell and I H Slater, 'Blocking of inhibitory adrenergic receptors by a dichloro analog of isoproterenol', J. Pharm. exp. Ther., 1958, 122: 480-8;
88. N C Moran and M E Perkins, 'Adrenergic blockade of the mammalian heart by a dichloro analogue of isoproterenol', J. Pharm. exp. Ther., 1958, 124: 223-37.
89. Vos, J. Pharm. Exp. Ther., op. cit., note 28 above, p. 77.
90. J D Fitzgerald, 'Trails of Discovery 1): The importance of chance and the prepared mind in the discovery of the beta-blockers', Dialogues in Cardiovascular Medicine, 2000, 5: 172-6, p. 172.
91. Kennedy, Dialogues in Cardiovascular Medicine, op. cit., note 6 above, p. 137.
92. J W Black, 'Drugs from emasculated hormones: the principles of synoptic antagonism' (Nobel Lecture, Dec. 8 1988), in T Frängsmyr (ed.), Nobel lectures in physiology or medicine, 1981-1990, Singapore, World Scientific, 1993, pp. 418-39, on pp. 418-19;
93. also M Weatherall, In search of a cure: a history of pharmaceutical discovery, Oxford University Press, 1990, pp. 240-1.
94. See Maxwell and Eckhardt, In Search of a Cure: A History of Pharmaceutical Discovery, op. cit., note 60 above, table 1, p. 12.
95. Maxwell and Eckhardt, In Search of a Cure: A History of Pharmaceutical Discovery, op. cit., Ibid., p. 13.
96. J M Cruickshank and B N C Prichard, Beta-blockers in clinical practice, 2nd ed., London, Edinburgh, Churchill Livingstone, 1994, esp. 'Historical Introduction', pp. 1-7, on pp. 2-3.
97. See Black's reminiscences on the occasion of his Nobel Prize, in J W Black, 'Biography of James W Black', in Frängsmyr (ed.), Beta-blockers in Clinical Practice, 2nd Ed., op. cit., note 65 above, pp. 413-17.
98. See also Fitzgerald, Beta-blockers in Clinical Practice, 2nd Ed., op. cit., note 63 above, pp. 174-5;
99. also M P Stapleton, 'Sir James Black and propranolol', Tex. Heart Inst. J., 1997, 24: 336-42, on pp. 338-9.
100. Vos, Tex. Heart Inst. J., op. cit., note 28 above, p. 83.
101. Black, 'Biography', in Frängsmyr (ed.), Tex. Heart Inst. J., op. cit., note 69 above, pp. 414-15.
102. K H George, 'James Black, English pharmacologist', in E J McMurray (ed.), Notable twentieth-century scientists, 4 vols, New York, Gale Research, 1995, vol. 1, pp. 185-7, on p. 185. George was obviously unaware that Black is Scottish, not English.
103. See also Black, 'Drugs from emasculated hormones', in Frängsmyr (ed.), Notable Twentieth-century Scientists, op. cit., note 65 above, p. 425.
104. Black, 'Biography', Notable Twentieth-century Scientists, op. cit., note 69 above, pp. 414-15.
105. Also Vos, Notable Twentieth-century Scientists, op. cit., note 28 above, p. 82.
106. Kennedy, Notable Twentieth-century Scientists, op. cit., note 6 above, p. 136.
107. Weatherall, Notable Twentieth-century Scientists, op. cit., note 65 above, p. 31.
108. Vos, Notable Twentieth-century Scientists, op. cit., note 28 above, pp. 78, 186.
109. Shanks, in a personal communication to Maxwell and Eckhardt, Notable Twentieth-century Scientists, op. cit., note 60 above, p. 13.
110. Gerskowitch, et al., Notable Twentieth-century Scientists, op. cit., note 4 above, p. 435.
111. Kennedy, Notable Twentieth-century Scientists, op. cit., note 6 above, p. 137;
112. Stapleton, Notable Twentieth-century Scientists, op. cit., note 69 above, p. 339.
113. Gerskowitch, et al., Notable Twentieth-century Scientists, op. cit., note 4 above, p. 435.
114. Fitzgerald, Notable Twentieth-century Scientists, op. cit., note 63 above, p. 172.
115. Black published his results in 1959. J W Black, 'Electrocardiographic changes produced in rabbits by vasopressin (pitressin) and their alteration by prolonged treatment with a commercial heart extract', J. Pharm. Pharmacol, 1960, 12: 87-94;
116. he also mentioned this research in his first report for ICI. ICI CPR 50: Research Department Report 50/3, 22 Jan. 1959.
117. Black, 'Biography', Frängsmyr (ed.), ICI CPR 50: Research Department Report, op. cit., note 69 above, p. 415, and personal communication.
118. ICI CPR 1: 8 Jul. 1951;
119. ICI CPR 3: 31 March 1948.
120. See Holland, ICI CPR, op. cit., note 12 above, p. 286;
121. also ICI CPR 2: Development Memo for Oct. 1957: visit of Veterinary Services Department to Glasgow Veterinary College and Hospital, 12 Nov. 1957.
122. Kennedy, ICI CPR 2: Development Memo for Oct. 1957, op. cit., note 6 above, pp. 136-7.
123. Johnson, et al., ICI CPR 2: Development Memo for Oct. 1957, op. cit., note 25 above, p. 585.
124. The importance of Horsfall's contribution was later recognized by having a new section, called the Biological Electronics Unit, created for him in the Biology/Biochemistry Department. ICI DO772: Administration Section organization chart, 18 March 1971.
125. Woodbridge, op. cit., note 18 above, p. 154 (based on an interview with Black).
126. In 1933, Fourneau synthesized piperoxane, the first of a new class of adrenergic blockers (Woodbridge, op. cit., ibid., p. 143).
127. Although the article in Comptes Rendus was not cited by Woodbridge, it is likely that it was E Fourneau and D Bovet, 'Recherches sur l'action sympatholytique de nouveaux dérivés du dioxane', C. r. Soc. biol. fil., 1933, 113: 388-90.
128. Vos, C. R. Soc. Biol. Fil., op. cit., note 28 above, p. 84.
129. The Swedish company A B Hassle, which merged first into Astra, and then with ICI's Pharmaceutical Division to form AstraZeneca, also picked up in 1963 the trail left by Fourneau, but unlike ICI did not abandon it (Vos, C. R. Soc. Biol. Fil., op. cit., ibid., p. 110).
130. More intriguingly still, in 1915 Fourneau had described the synthesis of phenoxypropanolamines, one of which was later synthesized by ICI and shown to be a beta-blocker. However, back in 1915, the effects of these compounds on the heart was thought to preclude them from being useful in the clinic. See Fitzgerald, C. R. Soc. Biol. Fil., op. cit., note 63 above, p. 174.
131. Black, 'Drugs from emasculated hormones', C. R. Soc. Biol. Fil., op. cit., note 65 above, p. 420.
132. Black, C. R. Soc. Biol. Fil., op. cit., Ibid., pp. 420-2.
133. See also J W Black, 'A personal view of pharmacology', Annu. Rev. Pharmacol. Toxicol, 1996, 36: 1-33, on pp. 2-3.
134. ICI CPR 26, ICI Pharmaceuticals Division Joint Report of Organic and Biochemical Sections (1954-7): 1 Jan.-31 March 1956.
135. ICI CPR 50: 50/3, 22 Jan. 1959.
136. ICI CPR 50: 1959. Ibid.
137. Barrett, ICI CPR 50, op. cit., note 60 above, p. 213.
138. ICI CPR 50/6: 14 June 1960.
139. Vos, ICI CPR, op. cit., note 28 above, p. 85.
140. Woodbridge, ICI CPR, op. cit., note 18 above, p. 176.
141. Woodbridge, ICI CPR, op. cit., Ibid., pp. 158, 177.
142. Although he had been at ICI for longer, Dunlop's name first appeared in connection with the cardiovascular programme in 1958. See ICI CPR 53/2: 22 Aug. 1958.
143. Barrett's name is first mentioned in ICI CPR 99 IB: Nov.-Dec. 1964 to Jan. 1965.
144. Barrett, ICI CPR, op. cit., note 60 above, p. 214.
145. ICI CPR 50/8: 21 Aug. 1961;
146. ICI CPR 56/8: 26 Jan. 1962.
147. ICI CPR 56/8: 26 Jan. 1962.
148. ICI CPR 50/9: 7 Nov. 1962.
149. ICI CPR 56/9: 7 Nov. 1962.
150. ICI CPR 56/9: 7 Nov. 1962.
151. The synthetic anti-histamines used at the time, such as mepyramine and diphenhydramine, did not inhibit the acid secretion stimulated by histamine, hence Black came up with the idea of finding a selective antagonist of histamine's "beta-receptors". See Gerskowitch, et al., ICI CPR, op. cit., note 4 above, p. 436.
152. NB: the first synthetic anti-histamines had in fact been developed by Daniel Bovet, working in Fourneau's laboratory in collaboration with Rhône-Poulenc. See V Quirke, 'War and change in the pharmaceutical industry: a comparative study of Britain and France in the twentieth century', special issue of Enterprise and History, 2004, 36: 64-83.
153. Vos, Special Issue of Enterprise and History, op. cit., note 28 above, p. 85.
154. Vos, Special Issue of Enterprise and History, op. cit., Ibid., pp. 90-1,
155. see also Vos's note 62, on p. 293.
156. Woodbridge, op. cit., note 18 above, pp. 182-3.
157. Woodbridge, op. cit., Ibid., p. 189.
158. L Finucane, SK&F: from Camberwell to Welwyn Garden City, 1956-1989, Welwyn Garden City, Smith Kline & French Laboratories Ltd., 1989, p. 49.
159. Paget's name first appears in connection with ICI's cardiovascular programme in 1959. See ICI CPR 50/4: 16 June 1959.
160. ICI CPR 56, 56/12: 24 Apr. 1964.
161. Woodbridge, ICI CPR, op. cit., note 18 above, pp. 191-3.
162. On Black's enduring influence, see Vos, ICI CPR, op. cit., note 28 above, p. 89.
163. Woodbridge, ICI CPR, op. cit., note 18 above, p. 193.
164. ICI CPR 99, 2B: Feb.-Apr. 1965;
165. CPR 99 3B: May-Aug. 1965.
166. ICI CPR 56/12: 24 Apr. 1964;
167. CPR 56/13: 13 Nov. 1964.
168. ICI CPR 56/13: 13 Nov. 1964.
169. Kennedy, ICI CPR, op. cit., note 6 above, p. 138;
170. Vos, ICI CPR, op. cit., note 28 above, p. 91.
171. B N C Prichard and P M S Gillam, 'Use of propranolol in the treatment of hypertension', Br. med. J., 1964, ii: 725;
172. Woodbridge, Br. Med. J., op. cit., note 18 above, p. 197.
173. See also L Hansson, 'The use of propranolol in hypertension: a review', in Hoffbrand, et al., Br. Med. J., op. cit., note 5 above, pp. 77-80.
174. Woodbridge, Br. Med. J., op. cit., note 18 above, pp. 212-13.
175. Woodbridge, Br. Med. J., op. cit., Ibid., p. 228.
176. According to Barrett, this is actually an impediment to therapeutic progress. Barrett, Br. Med. J., op. cit., note 60 above, pp. 217, 226.
177. Barrett, Br. Med. J., op. cit., Ibid., p. 217.
178. Not only was there Mead Johnson's sotalol, A B Hässle's alprenolol, but also Ciba's oxprenolol, which were all launched around the same time. Woodbridge, Br. Med. J., op. cit., note 18 above, pp. 198-203, 214.
179. ICI CPR 99, 5B: 25 May 1966.
180. ICI CPR 99, 9B: 6 Nov. 1967.
181. On the role of computers and information science in drug design, see P J Lewi, 'Computer technology in drug design', in E J Ariëns (ed.). Drug Design, New York, Academic Press, 1976, vol. 7, pp. 209-75.
182. ICI CPR 99, 13B: 27 March 1969.
183. Woodbridge, ICI CPR, op. cit., note 18 above, pp. 219-20.
184. Fitzgerald joined ICI in 1967. See ICI CPR 99, 9B: 6 Nov. 1967.
185. Woodbridge, ICI CPR, op. cit., note 18 above, pp. 232-5.
186. ICI CPR 99, 14B: 8 July 1969.
187. ICI CPR 99, 13B: 27 March 1969.
188. Membrane-stabilizing activity was later shown to be unimportant in beta-blockade. See Cruickshank and Prichard, ICI CPR, op. cit., note 68 above, p. 7.
189. Woodbridge, ICI CPR, op. cit., note 18 above, pp. 254-5.
190. Woodbridge, ICI CPR, op. cit., Ibid., pp. 258.
191. ICI CPR 99, 14B: 8 July 1969.
192. ICI CPR 99, 14B: 8 July 1969.
193. On the history of Ventolin, see E Jones, The business of medicine, London, Profile Books, 2001, pp. 330-3.
194. A technique by which fixed ligands bind the receptors in a solution, preventing their flow through a chromatography column, with the effect of separating them from other materials. See J D Robinson, Mechanisms of synaptic transmission: bridging the gaps (1890-1990), Oxford University Press, 2001, p. 159.
195. On the isolation of receptor protein from cell membranes, see J D Robinson, Mechanisms of synaptic transmission: bridging the gaps (1890-1990), 2001, ibid., pp. 157-63. Somerville found Lefkowitz's method difficult to reproduce, however.
196. ICI CPR 99, 25B: 27 Feb. 1973.
197. On the importance of quantitative-activity studies in the rise of a rational approach to drug design, see for instance Y C Martin, Quantitative drug design: a critical introduction, New York, Marcel Dekker, 1978.
198. ICI CPR 99, 23B: 16 June 1972.
199. ICI CPR 99, 22B: 7 March 1972.
200. On Hansch's method see Martin, ICI CPR, op. cit, note 143 above,
201. and also A Verloop, 'The use of linear free energy parameters and other experimental constants in structure-activity studies', in Ariens (ed.), ICI CPR, op. cit., note 60 above, pp. 133-88.
202. ICI CPR 99, 23B: 16 June 1972.
203. Unlike Black, Hässle's researchers believed that moderate beta-receptor stimulant action was useful in a beta-blocker, therefore it is likely that this change of position on ICI's part was a response to competitors' drugs coming onto the market. See Fitzgerald, ICI CPR, op. cit., note 63 above, p. 174.
204. ICI CPR 99, 23B: 16 June 1972.
205. ICI CPR B 99, 30B: 23 Oct. 1974.
206. ICI CPR B 99, 30B: 23 Oct. 1974.
207. On this progress from hypothetical entity to tangible object see E J Ariëns, 'Receptors: from fiction to fact', Trends Pharmacol. Sci. inaugural issue, 1979, pp. 11-15;
208. and R P Ahlquist, 'Adrenoceptors', in Trends Pharmacol. Sci. inaugural issue, ibid., pp. 16-17.
209. ICI CPR B 99, 33B: 20 Oct. 1975.
210. 2 receptors in 1967, concluding that while the former was prominent in cardiac stimulation, the latter played an important role in bronchodilation. A M Lands, et al., 'Differentiation of receptor systems activated by sympathomimetic amines', 1967, Nature, 214: 597-8.
211. See Robinson, Nature, op. cit., note 140 above, p. 154.
212. 2 receptors were mentioned in ICI's research reports was in CPR 99, 27B: 22 Oct. 1973.
213. ICI CPR B 99, 30B: 23 Oct. 1974.
214. ICI CPR B 99, 34B: 26 Feb. 1976.
215. ICI CPR 99, 1B: Nov.-Dec. 1964 to Jan. 1965.
216. ICI CPR B 99, 35B: July 1976.
217. l57 See Finucane, ICI CPR B, op. cit., note 112 above, ch. 10.
218. On the history of cimetidine, see also Maxwell and Eckhardt, ICI CPR B, op. cit., note 60 above, pp. 365-76;
219. and M Ennis and W Lorenz, 'Histamine receptor antagonists', in Parnham and Bruinvels (eds), ICI CPR B, op. cit., note 60 above, pp. 623-45.
220. Holland, ICI CPR B, op. cit., note 12 above, p. 288.
221. Holland, ICI CPR B, op. cit., Ibid., pp. 286-7.
222. On the parallels between the two projects, see Finucane, ICI CPR B, op. cit., note 112 above, p. 50.
223. Black, 'Biography', ICI CPR B, op. cit., note 69 above, p. 415.
224. Davey, ICI CPR B, op. cit., note 24 above.
225. D A Hounshell, 'Invention in the industrial research laboratory: individual act or collective process?', in R J Weber and D N Perkins, Inventive minds: creativity in technology, New York, Oxford University Press, 1992, pp. 273-90.
226. See A W Cuthbert, 'Men, molecules and machines', Trends Pharmacol. Sci. inaugural issue (1979): 1-3, on p. 3.