1906: Receptor Theory of Drug Action (1906)

At the turn of the 20th century, pharmacology was largely empirical: drugs were observed to produce
effects, but the cellular machinery underlying those effects was unknown. Two scientists working
independently provided the conceptual framework that would define the discipline for the next century.

Paul Ehrlich, studying the selective toxicity of arsenical dyes against trypanosomes in the 1890s,
coined the term "Rezeptor" to describe a cell-side binding site that could selectively engage a
drug molecule. His famous dictum—"Corpora non agunt nisi fixata" (substances do not act unless
fixed)—encapsulated the principle that a drug must bind to a cellular structure before it can
produce an effect. Ehrlich's concept of selectivity also led directly to his "magic bullet"
hypothesis and the rational search for selective chemotherapeutic agents.

John Newport Langley, working at Cambridge, arrived independently at similar conclusions through
a different route. Studying the actions of nicotine and curare on frog muscle preparations in 1905,
Langley demonstrated that these substances competed for the same tissue site—which he called the
"receptive substance"—without entering the muscle fibre itself. His 1906 paper formally introduced
the concept of a pharmacological receptor as a distinct molecular entity on the cell surface.

Together, Ehrlich and Langley's receptor theory provided the theoretical basis for quantitative
pharmacology. The concept was mathematised by A.J. Clark in the 1920s–1930s using occupancy theory
and later refined by Ariens, Stephenson, and Furchgott to incorporate efficacy, partial agonism,
and signal amplification. The receptor concept underpins every aspect of modern drug design, from
virtual screening to allosteric modulator development.