A binding question: the evolution of the receptor concept.

In present-day pharmacology and medicine, it is usually taken for granted that cells contain a host of highly specific receptors. These are defined as proteins on or within the cell that bind with specificity to particular drugs, chemical messenger substances or hormones and mediate their effects on the body. However, it is only relatively recently that the notion of drug-specific receptors has become widely accepted, with considerable doubts being expressed about their existence as late as the 1960s. When did the receptor concept emerge, how did it evolve and why did it take so long to become established?

Caught between the old and the new--Walther Straub (1874-1944), the question of drug receptors, and the rise of modern pharmacology.

This paper deals with an important development of scientific pharmacology, focusing on the reaction of the German pharmacologist Walther Straub to the receptor concept, which was a new approach to explain the binding of drugs to cells in the young discipline of pharmacology after 1900. The article analyzes how Straub as an important representative of his field between 1900 and 1944 was influenced by nineteenth-century thinking, and how he developed a rival physical theory to combat the receptor concept. Straub is seen as a man of transition, who on the one side tackled a core question of drug research with modern experimental methods, but on the other side was hardly able to accept new results in chemistry.

The quantification and differentiation of the drug receptor theory, c. 1910-1960.

While historians have dealt with the origins of the concept of drug receptors in the work of Paul Ehrlich (1854-1915) and John N. Langley (1852-1925) as well as with some of its applications in modern pharmaceutical research, the history of the receptor theory as such has been neglected. Discussing major developments and conceptual changes in receptor theory between about 1910 and 1960 (including relevant contributions by A. V. Hill, A. J. Clark, J. H. Gaddum, E. J. Ariëns and others), this paper attempts to fill this gap in historiography. It provides a case study of the unfolding of research under a new paradigm, but it considers also contemporary criticism and scepticism. By the early 1960s, quantitative investigations of drug action and interpretations of the experimental findings in terms of the receptor concept had become constitutive of the emerging field of 'molecular pharmacology'. Even then, however, receptors were still hypothetical entities.

[Historical foundations of the receptor concept in pharmacology]. / Historische Grundlagen des Rezeptor-Konzepts in der Pharmakologie.

In present-day pharmacology, the existence of specific cell receptors, which can combine chemically with drugs, poisons, neurotransmitters and hormones, is often taken for granted. However, until the 1960s receptors were controversial hypothetical entities. This article examines the initial experimental evidence for receptors that was produced and discussed between the 1870s and the 1930s. It is argued that pharmacologists were reluctant to adopt the receptor concept because of the indirect nature of the available experimental evidence, the competition with a physical theory of drug action and the fact that the idea of receptors had not originated from pharmacology itself, but from immunology and neurophysiology.

The emergence of the drug receptor theory.

Today, the concept of specific receptors for drugs and transmitters lies at the very heart of pharmacology. Less than one hundred years ago, this novel idea met with considerable resistance in the scientific community. To mark the 150th anniversary of the birth of John Newport Langley, one of the founders of the receptor concept, we highlight his most important observations, and those of Paul Ehrlich and Alfred Joseph Clark, who similarly helped to establish the receptor theory of drug action.

Pharmacological receptors: a century of discovery--and more.

A brief survey of the history of the development of the concept of the pharmacological receptor is presented. From the pioneering concepts of Paul Ehrlich, John Langley and others, receptors are described in terms of their recognition properties, their structures, transducing abilities and the impact of genomics and their role in contributing to genetic diseases. The receptor concept has firmly underpinned our advances in drug development and molecular medicine of the latter half of this century and it is clear that it will continue to drive pharmaceutical developments in the 21st century.

A personal view of pharmacology.

This essay is an account of the author's experience in trying to interpret the action of drugs as seen in in vitro bioassays. The central theme is how the development of simple mathematical models has assisted in the interpretation of drug actions. Starting from encounters with partial agonists, the essay describes the development of an operational model of agonist activity, the significance of receptor distribution, the analysis of indirect competitive antagonism and various two-receptor systems, followed by examples of pharmacological resultant activity. Analyses of tissue and species variations are described. The essay ends with an assessment of the future of bioassay in pharmacology.

[Imidazoline receptors. Historic review and current status of knowledge]. / Receptores imidazolínicos. Revisão histórica e estado actual dos conhecimentos.

After the initial demonstration, by Ruffolo in 1977, that imidazolines and phenethylamines do not interact in the same manner with adrenoceptors, a different class of receptors (imidazoline-preferring receptors) was identified. They are present in the brain stem and in several tissues at the periphery. This imidazoline-preferring receptor is believed to be the target of the anti-hypertensive effect of clonidine and the newly developed clonidine-related substances, rilmenidine and moxonidine. This review summarises the current knowledge and latest developments in this field, including the consensus on the nomenclature proposed by Ernsberger to classify the imidazoline receptors in I1 (clonidine and idazoxan sensitive) and I2 (idazoxan sensitive but clonidine insensitive) types.