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With the isolation of receptor proteins from cell membranes in the 1970s and the subsequent definition of receptor genes receptor theory became fact but a hundred years ago there was much controversy about the site and nature of drug action. In 1905 John Newport Langley, professor of physiology in Cambridge, described his concept of “receptive substances” as mediators of drug action in a paper in the Journal of Physiology that can be seen as the foundation of drug receptor theory (OpenUrlPubMed
In animal experiments in the 1870s Langley had shown that jaborandi, a plant extract containing pilocarpine, slowed the heart, the effect was reversed by atropine, and both effects were independent of vagus nerve function. Similarly pilocarpine stimulated the secretion of saliva and atropine inhibited it. In both heart and salivary gland experiments the effect depended on the amount of each drug present. Langley concluded that pilocarpine and atropine formed “chemical compounds” with tissue components, the end result depending on “their relative chemical affinity to the tissue and the mass of each present”. The drugs each reacted with the tissue cells one having a positive and one a negative effect [agonists and antagonists or inhibitors in modern terminology].
At the turn of the century there was considerable controversy about whether drugs such as nicotine, curare, pilocarpine, and atropine acted directly on muscle or gland cells or through nerve endings. In experiments on denervated striated muscle Langley showed that nicotine still produced tonic contraction that was relaxed by curare, and direct electrical stimulation of the muscle produced muscle contraction after injection of either drug. Langley wrote, “neither the poisons nor the nervous impulse act directly on the contractile substance of the muscle but on some accessory substance” and “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”. He was thus postulating the existence of receptors. Moreover, he generalised the idea, suggesting that all cells had a “chief substance” concerned with the cell’s main function, such as contraction or secretion, and receptive substances that were acted upon by chemical or nervous stimuli and regulated the metabolism of the chief substance. The theory of drug receptors had arrived. Ehrlich who had described “side chain” receptors in immunology was at first resistant to the idea of drug receptors but in 1907 he too proposed the existence of drug “chemoreceptors”. Langley’s theories were much debated at the time and receptors remained theoretical until the discoveries of the 1970s.
Langley was born in 1852 and died in 1925. He was a journal editor (Journal of Physiology, 1894–1925), scientific luminary (FRS 1883, president of the Neurological Society of Great Britain 1893, president of the physiological section, British Association for the Advancement of Science 1899, vice president, Royal Society 1904), and talented ice skater (he devised official rules for the sport and acted as an appeal judge in international competitions). He went to Cambridge as an undergraduate in 1871 and spent the whole of his career there.
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