The quantitative analysis of drug–receptor interactions: a short history

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Pharmacology started to develop into a real quantitative science in 1909, when A.V. Hill derived the Langmuir equation in the course of his studies on nicotine and curare. A history of the developments since then shows both brilliant insights and missed opportunities. It also shows that much remains to be done. There is still no mathematical description that can describe quantitatively the actions of agonists on G-protein-coupled receptors, although progress has been greater with agonist-activated ion channels, which are much simpler.

Section snippets

Physics, mathematics and receptors

The origins of pharmacology lie in therapeutics, as shown by its early history (e.g. [1]). But receptors are protein ‘machines’ and it was not long before attempts were made to describe receptor properties using the laws of physics. This needed a knowledge of physics, and of the mathematical methods used by physicists, which were uncommon among pharmacologists. It was not until A.V. Hill [2], a mathematician turned physiologist, took an interest in drug receptors in 1909 that this process got

Archibald Vivian Hill (1886–1977)

The first really quantitative attempt to understand the relationship between drug concentration and response came from studies in Cambridge, UK [2]. A.V. Hill was Scholar of Trinity College, Cambridge in 1909 when he derived the expression that is often referred to as the Langmuir equation, although Langmuir's work came several years later 3, 4. The title page of the paper that, arguably, started quantitative pharmacology is shown in Figure 2.

Hill became an undergraduate at Trinity College in

Alfred Joseph Clark (1885–1941)

A.J. Clark was almost the same age as Hill and they graduated in the same year (1909). Clark succeeded Arthur Cushny in the Chair of Pharmacology at UCL in 1919, and stayed there for seven years before moving to Edinburgh in 1926 [11]. Clark was medical by background and his early papers did not show his interests in quantitative pharmacology (his first paper was, like Hill's, published in 1909 but its title was ‘The detection of blood pigment in the faeces’).

Clark's interests in quantitative

John Henry Gaddum (1900–1965)

Gaddum, like Clark, started in medicine (at UCL in 1922), and went on to work for Henry Dale [19]. Gaddum, like Schild, worked on the statistics of biological assays but his claim to fame in the limited area dealt with here is his short communication to the Physiological Society in 1937 [16]. This was the first time that the equation for the competitive binding of two ligands to a receptor was written explicitly. For two competing ligands, A and B, the receptor occupancy by drug A can be

Heinz Otto Schild (1906–1984)

Schild was born in Fiume (now Rijeka, in Croatia), at a time when it was part of the Austro-Hungarian empire. In 1921, after the collapse of the Habsburg monarchy, his family moved to Munich, where he eventually graduated in medicine. In 1932, he moved to Dale's laboratory in London [20], and decided to stay in England when the Nazis came to power in 1933. After a period in Edinburgh, where he overlapped with Clark, Schild moved to UCL in 1937, where he stayed for the rest of his life, apart

Robert Stephenson (1925–2004)

Stephenson worked for most of his life in the Pharmacology Department in Edinburgh. In 1956 he published a paper [27] that attempted to make sense of the recently discovered phenomenon of partial agonism [28]. Stephenson's paper was prescient: he pointed out that, although a binding constant was sufficient to characterize an antagonist at equilibrium, it was not enough for an agonist. For an agonist, one needed to consider not only binding but also the ability of the agonist to produce a

Jeffries Wyman (1901–1995)

I think that, with hindsight, it could be argued that Wyman made a greater contribution to the understanding of conformational changes in receptors than any of the others mentioned here, although he never actually worked on receptors. He is the only American in my list of heroes, although the UCL connection seems inescapable even in his case. Wyman left Harvard Graduate School in 1924, and sailed on a slow steamer for England with John Edsall, 200 other passengers and 700 cattle ([34]; //stills.nap.edu/html/biomems/jwyman.html

Bernard Katz (1911–2003)

Katz was appointed to the chair of Biophysics at UCL in 1952, shortly after Biophysics had, at last, become a separate department. Katz was Hill's successor at UCL and the high regard he had for Hill is very obvious [5]. Katz described his arrival in London thus:

“I was born in March 1911 in the town of Leipzig in the middle of Germany. But I had a “re-birthday”, 24 years later, when I arrived at the port of Harwich in England, one afternoon in February 1935. I had escaped from Hitler's Reich,

More-recent developments

It was soon realized that single-ion-channel observations offered a way of dissecting apart the two steps in receptor activation that del Castillo and Katz had proposed: the binding step and the gating step. But to achieve this required new theoretical work to be done. Up to now, the mathematics has been essentially trivial: all macroscopic phenomena, however complex the reaction mechanism, can be expressed in a single equation [49], the vector of state occupancies being p(t)=p(0) exp(Qt),

Postscript

Pharmacology started as a branch of therapeutics, and that is still one important aspect of the subject. Alongside that, during the past 100 years, pharmacology has become a quantitative subject with a sound basis in the physical sciences. At the same time, enormous amounts have been learned about transduction mechanisms. The most common sort of receptor, the G-protein-coupled receptor family, has turned out to be more complex than Clark could have imagined. To this day, it is not possible to

Acknowledgements

I am very grateful to D.H. Jenkinson and L.G Sivilotti for helpful comments.

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