The Search For Nicotine Analogues

The documents show that, although the tobacco industry considered nicotine a mostly harmless drug, it was concerned about the potentially harmful effects of nicotine on the cardiovascular system. For example, nicotine acts directly on the heart and arteries, and carbon monoxide in the smoke reduces the ability of the blood to transport oxygen. The industry tried to solve this problem by looking for analogues to nicotine, drugs that could mimic the effects of nicotine on the brain without affecting the cardiovascular system. Although Philip Morris pursued this approach in the 1980s (4, 32), the documents show that BAT was interested in the problem in the early 1970s.

A decade before the first research report on nicotine analogues from BAT's R&DE (Research and Development Establishment) lab, Sir Charles Ellis described the research program the tobacco manufacturers in the United Kingdom were undertaking to investigate the cardiovascular toxicity of nicotine. In his keynote address at BAT's 1962 research conference in Southampton, Sir Charles said,

You are of course aware that smoking, by means of its nicotine content, is supposed to have an effect on the cardiovascular system. T.M.S.C. [Tobacco Manufacturers' Standing Committee] has agreed to contribute £12,000 over three years to Dr. Shillingford of the Cardiovascular Research Group of the Medical Research Council to enable them to extend their experiments to cover

the effects of nicotine. We think that it is well worth while having this work carried out by a skilled authoritative group with which we will have close contact.

It is the case that most previous work on the effects of nicotine on the cardiovascular system has been done with old techniques, and much of it is of doubtful quality. What T.M.S.C. believes is of particular importance is that Shillingford has developed entirely new techniques for analysing heart function and circulation in health and disease. These are based on observing changes in blood-flow by the use of short-lived radioisotopes which, for example, make it possible to measure the heart output every five minutes for an hour without using the old-fashioned catheter. You will be interested to know that Dr. Shillingford accepts the existence of beneficial effects of smoking and believes that although nicotine undoubtedly affects the cardiovascular system these effects are probably quite innocuous for normal healthy people [emphasis added]. {1102.01, pp. 19–20}

Concrete evidence of BAT's interest in nicotine analogues is documented in three research reports from the BAT Group Research and Development Centre in the 1970s {1205.11; 1205.13; 1208.03}. None of the reports indicate precisely what problem with nicotine the analogue work is designed to solve. However, when researchers for Philip Morris conducted a more extensive study of analogues in the 1980s, they were looking for compounds that had the central nervous system effects of nicotine while avoiding the cardiovascular effects (4, 32). BAT's concern with nicotine analogues may well have been based on the same considerations.

The abstract of the first of the three reports (written in November 1972) emphasizes the importance of the pharmacological actions of nicotine for smokers: "[T]he present scale of the tobacco industry is largely dependent on the intensity and nature of the pharmacological action of nicotine" {1205.11, p. 2}. The abstract emphasizes the need to develop acceptable substitutes should nicotine itself come to be regarded as unacceptable, and describes an analogue developed at Bath University through a postdoctoral fellowship supported by BAT. The summary reads as follows:

Should nicotine become less attractive to smokers, the future of the tobacco industry would become less secure.

Factors that could influence the attractiveness of nicotine are discussed, and it is concluded that substances closely related to nicotine in structure (nicotine analogues) could be important. Synthetic studies at Bath University have produced a compound that was shown by Bioassay Limited to have a powerful inhibitory effect on some of the pharmacological actions of nicotine.

It is recommended that this work continue with suitable collaborators to clarify some of the possible threats to, and opportunities for, the Company [emphasis added]. {1205.11, p. 1}

Although couched in somewhat hedged terms, the introduction amplifies the sentiment expressed in the summary and further discusses the importance of the pharmacological effects of nicotine.

It has been suggested that a considerable proportion of smokers depend on the pharmacological action of nicotine for their motivation to continue smoking [references omitted].

If this view is correct, the present scale of the tobacco industry is largely dependent on the intensity and nature of the pharmacological action of nicotine.

A commercial threat would arise if either an alternative product became acceptable or the effect of nicotine was changed.

An alternative product could come from the pharmaceutical industry. With a socially acceptable route for administration, and with medical endorsement, the product could be successful.

The effect of nicotine could be inhibited by an antagonist, and cigarettes would tend to become insipid. Such an antagonist could arise by accident or design from the pharmaceutical industry. It might be used tactically to advance that industry's alternative product, or its general use could be advocated by the anti-smoking lobby, with or without government support [emphasis added]. {1220.01, p. 2}

The concern about a "commercial threat" might be related to the work reported by Murray Jarvik earlier that year at a CTR-sponsored symposium on nicotine-blocking drugs (33). Jarvik's experiments, which had been supported by the American Cancer Society, included one on nicotine-blocking agents. He reported that a centrally acting agent called mecamylamine, which blocks the effects of nicotine in the brain, was associated with a compensatory increase in smoking in a short-term experiment. However, over time, such a blocking drug would be expected to reduce the attraction of smoking by preventing the reinforcing effects of nicotine on the central nervous system. In this way, smokers would become less and less compulsive about the use of tobacco products. Mecamylamine itself was unsuitable as a therapeutic agent because it also caused a marked lowering of blood pressure. However, Jarvik's experiment held an obvious lesson for BAT: conventional pharmaceutical companies might be able to market a safe nicotine antagonist that would prevent the nicotine in tobacco products from doing its thing. The nicotine analogue work may have been seen as a way to get ahead of this disturbing possibility.

The abstract of a second report, from 1973, indicates that the work did, in fact, continue, at least to some extent. The abstract describes the pharmacological activity of an isomer of a previously synthesized analogue {1205.13}. In this instance, the synthetic work had been performed at the School of Pharmacy of London University. The full reports are not available.

The third report, dated June 10, 1979, describes the testing of an analogue, including tests on muscle tissue {1208.03}. This may have been a screening test for cardiovascular activity, since Dr. Victor DeNoble indicated that tests of smooth-muscle reactivity had served this function in the Philip Morris research program (32). The results in this instance were not encouraging, but there seem to have been plans to test additional compounds.