Although he was writing almost 20 years before the first detailed structural account of any receptor, at a time when our knowledge of receptor mechanisms was slight, this concept had already spawned many outstanding pharmaceutical innovations. One thinks, for example, of the development of beta-blockers and of selective histamine antagonists. So how did this most influential idea come about?
The notion that drugs act through receptors has its true origins in the late nineteenth century, when dogma held that the cell protoplasm is a single, very large, molecule. Paul Ehrlich introduced the term 'receptor' in 1900 to describe sites on this molecule to which bacterial toxins (and, later, drugs) bind to bring about changes in cellular metabolism. The idea of discrete and specific binding sites was also supported by the experiments of John Newport Langley. His observations on the antagonistic actions of curare and nicotine on skeletal muscle eventually led to the key concept that drugs possess two properties: the ability to bind to the 'receptive substance' (as he called it) or affinity; and the ability of an agonist to cause an effect, later dubbed its efficacy. The final impetus came from Alfred Joseph Clark, who realized that the relationship between drug concentration and response could be described using a simple mathematical model, and who thus bequeathed us the rudiments of receptor theory.
