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Winning the battle of histamine antagonists


Comparing the stories of beta blockers and histamine
James Black Scientist
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I think I mentioned that the chemists were making analogues and derivatives of histamine, mainly concentrating on the imidazole ring, and one of the first things they did, the chemists, was to put methyl groups in every position, on the side chain, on the nitrogen. So methyl groups on the nitrogen just gave potent agonists which were longer lasting. Methyl groups on the ring either did nothing or in the 4 position of the ring, 4-methylhistamine, it became selective just for acid secretion. So it was like it was two histamines, if you like, what isoprenaline was to the beta receptors. And really that was the thin gruel which kept us going for 4 years – was 4-methylhistamine – and then 2-methylhistamine was selective the other way round.

Anyway, so the whole point of the story... I'll go back now and compare beta blocking story with the histamine story. As far as ICI [Imperial Chemical Industries] was concerned I... my recollection is that I promised them nothing other than if I was successful they had... would have a tool to answer a question, and I didn't know what way the conical question would fall out. It so happened that it fell out in their favour. And so, when we come to the histamine story, that's a different story altogether. This goes back now to 1905 when a substance, which claimed to be a substance, when gastrin was described as a substance you could extract from the mucous membrane of the gastric antrum and that... which stimulates acid secretion. Now, that discovery, if that's what it was, was shadow... overshadowed very quickly because the discovery of histamine would do the same kind of things which gastrin was claimed to do – lowering blood pressure, stimulating acid – and so there was confusion for many years about the relationship between gastrin and histamine. But by the time we got involved in this work, six... in the 60s, gastrin as a chemical entity was established. We knew it was peptide and we knew it was different. So there was histamine, there was gastrin, and also there was people like, Code arguing that gastrin acted by releasing histamine locally, and other people thought: rubbish. And so, again, the story that we put to Smith Kline – Bill – was, well, I don't know whether this is going to work because if histamine is not physiologically involved, there was this paper, Gastric Secretion: No Room for Histamine, and so... so it was just a pharmacological by-product. And so I couldn't be certain that if gastrin, which was the main stimulant... physiological stimulant of that secretion, wasn't acting through histamine, then a... an H2 antagonist wouldn't block it, but that was the thing we ought to be able to get an answer. And so we couldn't really be sure that it was going to work, but of course it did. So that was illuminating to the gastrin rhesus histamine story, which is pretty well known; standard dogma in acid secretion.

The late Scottish pharmacologist Sir James W Black (1924-2010) revolutionised medical treatment of hypertension and angina with his invention of propranolol, the first ever beta blocker. This and his synthesis of cimetidine, used for the treatment of peptic ulcers, earned him the Nobel Prize in Physiology or Medicine in 1988.

Listeners: William Duncan

After graduating with a BSc Bill Duncan went on to gain a PhD from Edinburgh University in 1956. He joined the Pharmaceuticals Division of ICI where he contributed to the development of a number of drugs. In 1958, he started a collaboration with Jim Black working on beta blockers and left ICI with him in 1963 to join the Research Institute of Smith Kline & French as Head of Biochemistry. He collaborated closely with Black on the H2 antagonist programme and this work continued when, in 1968, Duncan was appointed the Director of the Research Institute. In 1979, he moved back to ICI as Deputy Chairman (Technical), a post he occupied until 1986 when he became Chairman and CEO of Coopers Animal Health. He ‘retired’ in 1989 but his retirement was short-lived and he held a number of directorships in venture capital backed companies. One of his part-time activities was membership of the Bioscience Advisory Board of Johnson and Johnson who asked him to become Chairman of the Pharmaceutical Research Institute of Johnson and Johnson in New Jersey. For personal reasons he returned to the UK in 1999, but was retained by Johnson and Johnson until 2006 in a number of senior position in R&D working from the UK. From 1999 to 2007 he was a non-executive director of the James Black Foundation. He is now fully retired.

Tags: ICI, 1905, 1960s, Smith, Kline & French, Control of Gastric Secretion: No Room for Histamine, CF Code

Duration: 4 minutes, 4 seconds

Date story recorded: August 2006

Date story went live: 02 June 2008