Side-chains and receptive substances
The role of Paul Ehrlich (1854–1915) in the development of the receptor concept is quite well-known [10], and I will therefore only briefly sketch it here (Figure 2). Ehrlich's side-chain-theory formed an important basis for his work on blood cells and on chemotherapy of infectious diseases such as sleeping-sickness and syphilis. In 1910, his research led to the introduction of Salvarsan, the famous ‘magic bullet’ against the germs of syphilis. Ehrlich's side-chain-theory was developed in the course of his studies into the staining of body cells and tissues, into the oxygen consumption of cells, and especially on the interaction between bacterial toxins and the so-called anti-toxins or antibodies formed by the body. In 1897 Ehrlich published for the first time a full account of his side-chain-theory of anti-toxin formation. The large ‘molecule’ of the cell protoplasm was supposed to have certain side-chains that were able to bind chemically the toxins produced by the bacteria. The thus occupied side-chains became unable to fulfil their usual functions in nutrition and oxygen consumption, forcing the cell to produce more side-chains. A surplus of side-chains was released into the blood stream where they bound as anti-toxins or antibodies to the bacterial toxins—forming thus the basis of immunity (Figure 3). In 1900 Ehrlich replaced the term side-chain (or Seitenkette) with the term Receptor [11].
However, Ehrlich initially believed that receptors existed only for toxins and for physiological foodstuffs and ferments. Drugs and medicines could quite easily be washed out of body tissues with solvents, so that he did not assume that they were fixed to specific components of the cell. He changed his mind only in 1907 [12], partly due to results of his own further research, but in particular also because of a different kind of receptor theory that had been proposed by the Cambridge physiologist John Newport Langley (1852–1925) (Figure 4). Langley's concept is particularly interesting because it placed special importance on the notion of substance and of substance binding.
In the mid-1870s, as a student of Michael Foster (1836–1907), Langley had been given the task of studying the effects of the plant drug jaborandi in animals, in particular its effect on the heart. Foster was interested in whether the automatic activity of the heart originated from its own muscle fibres or from nerves leading to the heart. Langley showed that the effect of jaborandi – a slowing down of the heart beats – occurred when the heart nerves were paralyzed using curare. He also demonstrated that the effect of jaborandi could be reversed by dripping a solution of atropine directly on the exposed animal heart. Both these findings indicated that the drug jaborandi acted directly on the heart muscle and, to a certain extent, supported Foster's view that the automatic heart beat probably originated from within the heart muscle itself [13].
This led Langley to pursue two lines of research that were also of interest to other physiologists of the time: one was the question whether pharmacological substances act directly on the body tissues or indirectly by affecting the endings of nerves leading into these tissues; the other was the question how antagonistic action between drugs, for example the one Langley had shown between jaborandi and atropine, came about. In a further series of experiments, he demonstrated the antagonism between pilocarpine (an alkaloid of jaborandi) and atropine on salivary secretion in dogs and cats; pilocarpine stimulated secretion, atropine stopped it, a new dose of pilocarpine got it going again, a further dose of atropine stopped it, and so on. How could this be explained? Obviously the relative concentration of the two substances in the animal body played a role, and both substances had to have a chemical affinity to the relevant tissues. In 1878 Langley formulated the following hypothesis:… 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[14].
In other words, Langley used the analogy between two inorganic chemical substances competing for reaction with the same third inorganic substance as a model to explain antagonistic drug action in the body. This implied that the relevant body cells contained some specific substances to which the drug substances had a chemical affinity. This thought, as we shall see, formed the basis of his later receptor concept.
Langley formulated his receptor concept only about 30 years later, because his research path led him into other areas, in particular into the physiology of the autonomic nervous system, a field in which he became an international authority. However, his neurophysiological research led him eventually back to the question of drug antagonisms.
The key experiment for his receptor concept involved the antagonism between nicotine and curare and was carried out on an anaesthetized rooster. Injection of nicotine led to a characteristic contraction of certain muscles of the leg, recognizable in the stiff, extended legs of the animal. This effect could be antagonised by injecting curare, resulting in the relaxation of the leg muscles. This antagonism could also be shown if the relevant nerves of the leg muscles had been cut through and allowed to degenerate, which meant for Langley that the two drugs acted on the muscle tissue directly. Just like pilocarpine and atropine, nicotine and curare competed for the same substances in the protoplasm of the cells. Moreover, after application of curare the relaxed leg muscles could be made to contract by applying an electric current. Langley concluded from this finding that neither the drugs nor the electric stimulus acted directly on the contractile substance of the muscle cells, but on what he called ‘accessory substances’. 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 [15]’.
This statement, made in 1905, was the first clear formulation of Langley's receptor concept. He was very quick to generalize it, suggesting that it could be applied to explain also the action of other alkaloids, such as pilocarpine, atropine and strychnine, and of hormones, such as adrenalin, secretin, thyroidin and the sex hormones. And he wrote in general terms: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 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[16].
Langley was aware of the similarity between his concept of receptive substances in cells and Paul Ehrlich's side-chain theory. However, he maintained that they had uncovered somewhat different phenomena. Both assumed, as he put it, ‘atom-groups of the protoplasm’ of the cell, to which substances could bind. But while Ehrlich's side-chains were ‘fundamental’ to the cell's life (i.e. the cell would die if they were all occupied by poisons), Langley's ‘receptive substance’ merely modified the cell's function when a drug or hormone bound to it. Significantly, Langley never adopted Ehrlich's more general term ‘receptor’, but stuck to his own term ‘receptive substances’ throughout his life. Ehrlich, on the other hand, conceded that the receptor concept was also applicable to drugs and medicines, not only to toxins or foodstuffs.