“Receptive Substances”: John Newport Langley (1852–1925) and his Path to a Receptor Theory of Drug Action

Abstract

The concept of specific receptors that bind drugs or transmitter substances onto the cell, thereby either initiating biological effects or inhibiting cellular functions, is today a cornerstone of pharmacological research and pharmaceutical development. Yet, while the basic ideas of this concept were first explicitly formulated in 1905 by the Cambridge physiologist John Newport Langley (1852–1925), drug receptors remained hypothetical entities at least until the end of the 1960s. Without doubt, the development of receptor-subtype specific pharmaceuticals—especially the beta-adrenergic receptor antagonist propranolol (introduced in 1965)—promoted the acceptance of the receptor concept in pharmacology. It was only in the 1970s, however, that receptors began to be isolated as specific proteins of the cell membrane and that their composition and conformation began to be explored. During the last twenty years the modern techniques of molecular biology have helped to determine the genetic basis of receptor proteins, to identify their amino acid sequences, and to further elucidate their remarkable structural diversity as well as their similarities and evolutionary relationships. Numerous receptor types and subtypes have since been characterized.

The Hill equation and the origin of quantitative pharmacology

“…This breakthrough occurred in the context of the receptor theory, a hypothesis that had emerged just before the birth of quantitative pharmacology. The suggestion that both exogenous and endogenous agents must be specifically bound to structures inherent to the living organisms before exerting an effect was first proposed by John Newport Langley in 1878, based on his experiments on salivary secretion in the dog (Maehle 2004). Paul Ehrlich (1854-1915) developed a similar hypothesis starting from the results of his bacteriological investigations in 1897 (Maehle 2009).…”

“…Paul Ehrlich (1854-1915) developed a similar hypothesis starting from the results of his bacteriological investigations in 1897 (Maehle 2009). They refined these ideas in close competition, which is also reflected in the terms they used to describe the specific chemical structure on the cell receiving the agent evoking a cellular response: "side chain" (Ehrlich in 1897), "receptor" (Ehrlich in 1900; the term proved to be enduring), and "receptive substance" (Langley in 1905) (Maehle 2004(Maehle , 2009). The receptor concept can be summarized by the classic maxim of Ehrlich: "Corpora non agunt nisi fixata" (agents do not act unless they are bound) (Pelner 1972).…”

Hormones

“…The autonomic nervous system [105], as part of the peripheral nervous system, acts largely independent of conscious control (involuntarily); it serves to maintain the organism's internal balance (circulation, breathing, peristalsis, muscle tone and secretion), and controls also visceral functions. According to Walter Holbrook Gaskell (1847-1914), the autonomic nervous system is sub-divided into two branches, which he named sympathetic and parasympathetic nervous system, in relation to their morphology and function.…”

Beta-Adrenergic Receptors, from Their Discovery and Characterization through Their Manipulation to Beneficial Clinical Application

“…John Newport Langley (1852–1925), a physiologist at Cambridge in the early 1900s, first proposed the challenging concept of specific receptors that bind drugs or transmitter substances onto the cell, thereby either initiating biological effects or inhibiting cellular functions within the cell itself [4,5]. Around the same time it was postulated by Paul Ehrlich (1854–1915) that these receptors were selective.…”