John Newport Langley and Paul Ehrlich introduced the concept of a receptor that would mediate drug action at the beginning of the 20th century. Alfred Joseph Clark was the first to quantify drug-induced biological responses (specifically, f-mediated receptor activation).
What is the history of pharmacological receptor theory?
Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that would mediate drug action at the beginning of the 20th century.
What are receptors?
Introduction The receptor concept is to pharmacology as homeostasis is to physiology, or metabolism to biochemistry. They provide the basic framework, and are the ‘Big Ideas' without which it is impossible to understand what the subjects are about.
What is Ehrlich’s theory of receptors?
Paul Ehrlich, a contemporary of Langley working in Frankfurt, came to the idea of receptors from his interest in the immunology and chemotherapy of infectious diseases. His idea was that bacterial toxins combine with nutrient-capturing structures of cells (‘sidechains’), thus starving them.
Is 'receptor theory' still relevant?
Though some simple quantitative rules of ‘receptor theory' are still useful, the current emphasis is on unravelling the pathways that link receptors to responses, and it will be some time before we know enough about them to embark on the next phase of ‘receptor theory'.
Who are the pioneers in receptor function?
What is the receptor concept?
What did Clark and Gaddum find about competitive antagonism?
What is Clark's agonist/antagonist ratio?
What were the two breakthroughs in the development of the receptor?
How did Paul Ehrlich come up with the idea of receptors?
What is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism?
See 4 more
About this website
What is the concept of receptors?
(reh-SEP-ter) A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific effect in the cell.
What theory did Clark and gaddum develop?
Occupation Theory Proposed by Gaddum and Clark, the theory states that the intensity of pharmacological effect is directly proportional to the number of receptors occupied by the drug.
What are theories of drug receptors?
A drug's ability to affect a given receptor is related to the drug's affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity—degree to which a ligand activates receptors and leads to cellular response).
What is classical receptor theory?
Classical receptor-theory presents models of the relation between drug concentration and biological effect, also in the case where more than one binding site on a receptor must be occupied by the agonist to evoke a response.
Who discovered receptors?
Abstract. It is nearly one hundred years since John Langley of Cambridge developed the idea of the 'receptive substance' or 'receptors' as we now call them.
What is the hypothesis of Clark?
Hypothesis of Clark. The pharmacologic effect depends on the percentage of receptors occupied. The drug must have affinity for the receptor. If all receptors are occupied, maximum effect is obtained.
When was the concept of drug receptor introduced?
Gaddum (1937) derived for the first time the equation describing the binding of two drugs at the same receptor. This idea was further developed in an important paper by Schild (1947) published appropriately in a very early volume of the BJP.
What are the 4 types of receptors?
Receptors can be subdivided into four main classes: ligand-gated ion channels, tyrosine kinase-coupled, intracellular steroid and G-protein-coupled (GPCR).
What are the types of receptors?
Cell-surface receptors come in three main types: ion channel receptors, GPCRs, and enzyme-linked receptors. Ion channel receptors: When a ligand binds an ion channel receptor, a channel through the plasma membrane opens that allows specific ions to pass through.
What is allosteric theory?
A simple theoretical model of allosteric receptor function whereby the receptor activates cellular response machinery according to an operational equilibrium dissociation constant KE under normal circumstances and with a dissociation constant K'E when bound to the allosteric modulator.
What is a receptor site in pharmacology?
A drug receptor is a specialized target macromolecule that binds a drug and mediates its pharmacological action. These receptors may be enzymes, nucleic acids, or specialized membrane-bound proteins. The formation of the drug-receptor complex leads to a biological response.
What is the nature of binding between drug and receptor?
Molecules (eg, drugs, hormones, neurotransmitters) that bind to a receptor are called ligands. The binding can be specific and reversible. A ligand may activate or inactivate a receptor; activation may increase or decrease a particular cell function. Each ligand may interact with multiple receptor subtypes.
What are the relevance of drug receptor theories?
A drug receptor is a specialized target macromolecule that binds a drug and mediates its pharmacological action. These receptors may be enzymes, nucleic acids, or specialized membrane-bound proteins. The formation of the drug-receptor complex leads to a biological response.
What is allosteric theory?
A simple theoretical model of allosteric receptor function whereby the receptor activates cellular response machinery according to an operational equilibrium dissociation constant KE under normal circumstances and with a dissociation constant K'E when bound to the allosteric modulator.
What is meant by occupancy theory?
Clark's occupancy theory is based on the idea that the fraction of total receptors bound by a ligand is directly proportional to the response.
What is occupation theory?
It argues that occupation fulfils basic human needs essential for survival, provides the mechanism for people to exercise and develop innate capacities of a biological, social and cultural nature, to adapt to environmental changes, and to flourish as individuals.
Principles: Receptor theory in pharmacology
This uniformity allowed quantitative experimentation that could be cross-checked in many laboratories; the resulting data laid the groundwork for modern receptor
Biopharmaceutics Flashcards | Quizlet
Study with Quizlet and memorize flashcards containing terms like The termination of action of a drug is determined by: A.Excretion of intact active molecule B.Excretion of inactivate molecule C. Tissue redistribution D. A & C, Pharmaceutical equivalents are drug products that contain: A. Identical amounts of active drugs B. Identical amounts of inactive ingredients C. Identical amounts of ...
Receptor Theory - an overview | ScienceDirect Topics
According to receptor theory the in vivo potency (i.e., the EC 50) and intrinsic activity (i.e., α) are dependent on multiple factors related to the drug (receptor affinity, intrinsic efficacy) and the biological system (receptor density, transducer function relating receptor occupancy to the pharmacological effect) (Figure 2).The prediction of in vivo drug concentration–effect ...
Introduction to Receptor Pharmacology - Reach Cambridge
common first messengers for receptors •gases (NO, H 2 S) •Small inorganic ion (eg. Ca2+) •Proteins & peptides (various hormones, growth factors)
Who introduced the concept of a receptor that would mediate drug action at the beginning of the 20th century?
Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that would mediate drug action at the beginning of the 20th century.
Which scientist showed that adrenaline has receptor-mediated effects?
However, it was only when Ahlquist showed the differential action of adrenaline demonstrated its effects on two distinct receptor populations, did the theory of receptor-mediated drug interactions gain acceptance.
What are the postulates of receptor theory?
Postulates of receptor theory 1 Receptors must possess structural and steric specificity. 2 Receptors are saturable and finite (limited number of binding sites) 3 Receptors must possess high affinity for its endogenous ligand at physiological concentrations 4 Once the endogenous ligand binds to the receptor, some early recognizable chemical event must occur
What did Langley discover about the receptor?
In 1901, Langley challenged the dominant hypothesis that drugs act at nerve endings by demonstrating that nicotine acted at sympathetic ganglia even after the degeneration of the severed preganglionic nerve endings. In 1905 he introduced the concept of a receptive substance on the surface of skeletal muscle ...
What was the flaw in Clark's receptor-occupancy model?
The flaw in Clark's receptor-occupancy model was that it was insufficient to explain the concept of a partial agonist. This led to the development of agonist models of drug action by Ariens in 1954 and by Stephenson in 1956 to account for the intrinsic activity (efficacy) of a drug (that is, its ability to induce an effect after binding).
What was Ehrlich's theory of selectivity?
He theorized that selectivity was the basis of a preferential distribution of lead and dyes in different body tissues. However, he later modified the theory in order to explain immune reactions and the selectivity of the immune response.
When was the receptor occupancy model first described?
It was first described by Black and Leff in 1983 as an alternative model of receptor activation. Similar to the receptor occupancy model, the theory originated from earlier work by del Castillo & Katz on observations relating to ligand-gated ion channels.
What is the receptor concept?
The receptor concept is to pharmacology as homeostasis is to physiology, or metabolism to biochemistry. They provide the basic framework, and are the ‘Big Ideas’ without which it is impossible to understand what the subjects are about. Try to imagine a pharmacology course that made no mention of receptors.
How did Paul Ehrlich come up with the idea of receptors?
His idea was that bacterial toxins combine with nutrient-capturing structures of cells (‘sidechains’), thus starving them. The cells respond by making more of these sidechains, some of which escape into the circulation as ‘antibodies’ that combine with the toxin and make it harmless. He later suggested that the sidechains of bacteria differed from those of the host, and went on to study synthetic molecules, based on aniline dyes, that might act selectively on these bacterial sidechains, an endeavour that ended triumphantly with the discovery of Salvarsan in 1909, the first effective treatment for syphilis.
When were nicotinic acetylcholine receptors first identified?
Around this time also, nicotinic acetylcholine receptors were first successfully labelled with α -bungarotoxin ( Miledi et al., 1971 ), and β -adrenoceptors with alprenolol ( Alexander et al., 1975 ), leading to the purification, sequencing and cloning of all these receptors and several others.
How do living organisms use chemical signals?
Living organisms are chemical machines, and rely on chemical signalling within and between cells, at long or short range, through the agency of ligands and receptors. Understanding the processes involved in these signalling pathways is therefore crucial to understanding biology.
What is chemical signalling?
Abstract. Chemical signalling is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism. Chemical recognition is the function of receptors, which, in addition to recognising endogenous chemical signals, are also the target of many important experimental and therapeutic drugs.
When was the first drug discovery?
Pharmacology took up this challenge before anything was known about chemical structure, and when ‘drugs’ were all either natural products of uncertain composition or inorganic substances such as mercury or arsenic salts. It was only after Kekulé discovered the structure of the benzene ring in 1865, and the now familiar 2-dimensional representations of the structure of organic molecules began to appear – the first in 1868 – and the chemical structures of natural products began to be defined, that the idea of specific ‘lock-and-key’ relationships between drugs and their receptors could emerge from the shadows. It had actually been envisaged, in a philosophical way, centuries earlier. For example, John Locke in his Essay concerning human understanding (1690) wrote:
When was pharmacology first developed?
Pharmacology as a scientific discipline was born in the mid-19th century, amid the great biomedical resurgence of that period (see also Cuthbert, this issue). The world's first pharmacology department was set up by Buchheim in 1847, in recognition of the need to understand how therapeutic drugs and poisons produced their effects. The inadequacy (or, more precisely, ‘inverse adequacy’ to use today's receptor parlance) of therapeutic drugs at the time was summed up in Oliver Wendell Holmes’ comment in 1860: “… if the whole materia medica as now used could be sunk to the bottom of the sea, it would be all the better for mankind – and the worse for the fishes”. The challenge for pharmacology was clear. It had, then as now, to apply scientific principles to make medicines more effective and less dangerous.
Who were the two proponents of the concentric zone model?from quizlet.com
Karl Marx and Friedrich Engels were proponents of the concentric zone model.
What did Freud focus on?from quizlet.com
Freud himself focused on the study of criminal behavior.
What is the term for those who advocate conflict theories and class and power inequality as the causes of crime?from quizlet.com
Those who advocate conflict theories and class and power inequality as the causes of crime are known as radical criminologists.
Who were the two proponents of the concentric zone model?
Karl Marx and Friedrich Engels were proponents of the concentric zone model.
What did Freud focus on?
Freud himself focused on the study of criminal behavior.
What is the term for those who advocate conflict theories and class and power inequality as the causes of crime?
Those who advocate conflict theories and class and power inequality as the causes of crime are known as radical criminologists.
Who developed the receptor theory?
... The receptor theory of drug action was essentially formulated during the first three decades of the 20th century through the endeavours of Paul Ehrlich in Germany and John Newport Langley, Alfred Joseph Clark and Sir John Henry Gaddum in England (Clark, 1933; Rang, 2006). Towards this end, Paul Ehrlich characterized mast cells (Ehrlich, 1879) and introduced the term 'receptor' to refer to the diverse cellular 'receptive substances' that were assumed by J.N. Langley to dose-dependently mediate the antagonistic effects of pharmacologically active compounds (Ehrlich and Morgenroth, 1900). ...
How are pharmacological responses modulated?
Pharmacological responses are modulated over time by regulation of signaling mechanisms. The canonical short-term regulation mechanisms are receptor desensitization and degradation of the response. Here for the first time a pharmacological model for measuring drug parameters is developed that incorporates short-term mechanisms of regulation of signaling. The model is formulated in a manner that enables measurement of drug parameters using familiar curve fitting methods. The efficacy parameter is k τ , which is simply the initial rate of signaling before it becomes limited by regulation mechanisms. The regulation parameters are rate constants, k DES for receptor desensitization and k D for response degradation. Efficacy and regulation are separate parameters, meaning these properties can be optimized independently of one another in drug discovery. The parameters can be applied to translate in vitro findings to in vivo efficacy in terms of the magnitude and duration of drug effect. When the time course data conform to certain shapes, for example the association exponential curve, a mechanism-agnostic approach can be applied to estimate agonist efficacy, without the need to know the underlying regulatory mechanisms. The model was verified by comparison with historical data and by fitting these data to estimate the model parameters. This new model for quantifying drug activity can be broadly applied to the short-term cell signaling assays used routinely in drug discovery and to aid their translation to in vivo efficacy, facilitating the development of new therapeutics. Highlights Regulation of signaling impacts measurement of drug effect Receptor desensitization is incorporated here into a kinetic model of signaling Drug effect and signaling regulation can now be measured independently The analysis framework is designed for signaling assays used in drug discovery These new analysis capabilities will aid development of new therapeutics
How does agonist binding affect biological activity?
The processes by which agonist binding promotes biological activity is a key issue in G protein-coupled receptor (GPCR) pharmacology, with much of our understanding governed by the application of mathematical models to experimental data. Models are built upon decades of fundamental principles, providing key concepts and measurable parameters which quantify agonism. Whilst numerous general receptor activation models exist, such as the operational model of agonism, there is no single model capable of describing all functional effects. Instead, there are a variety of models, each employed to understand specific experimental observations. In this review, we summarise recent GPCR models which incorporate: multiple signalling pathways simultaneously, constitutive receptor activity, or receptor dynamics, whilst providing parameters to quantify agonist bias. We also describe how model parameterisation requires model organisms and advanced experimental techniques, both proving invaluable for the construction of more complex, mechanistic models.
What do experimental pharmacologists use to describe biological observations?
Experimental pharmacologists rely on the application of models to describe biological observations in order to learn about a drug's effective concentration, the strength with which it binds its target and drives a response (at either molecular or system level), and the nature of more complex drug actions (allosterism/functional selectivity). Models in current use build upon decades of basic principles, going back to the beginning of the last century. Yet often, researchers are only partially familiar with these underlying principles, creating the potential for confusion due to failure to recognise the underpinning assumptions of the models that are used. Here, we describe the history of receptor theory as it underpins receptor stimulus‐response models in use today, emphasising particularly attributes and models relevant to G protein‐coupled receptors – and point to some current aims of model development.
What is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism?
Chemical signalling is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism. Chemical recognition is the function of receptors, which, in addition to recognising endogenous chemical signals, are also the target of many important experimental and therapeutic drugs. Receptors, therefore, lie at the heart of pharmacology. This article describes the way in which the receptor concept originated early in the 20th century, and evolved through a highly innovative stage of quantitative theory based on chemical kinetics, to the point where receptors were first isolated and later cloned, until we now have a virtually complete catalogue of all the receptors present in the genome. Studies on signal transduction are revealing great complexity in the events linking ligand binding to the physiological or therapeutic response. Though some simple quantitative rules of ‘receptor theory’ are still useful, the current emphasis is on unravelling the pathways that link receptors to responses, and it will be some time before we know enough about them to embark on the next phase of ‘receptor theory’. British Journal of Pharmacology (2006) 147, S9–S16. doi:10.1038/sj.bjp.0706457
How do living organisms interact with chemical compounds?
Living organisms interact with various chemical compounds via receptors, which is described by the receptor theory. The affinity of the biologically active compounds toward receptors and their ability to trigger a biological or toxic signal vary substantially. In this work, we describe a new insight into understanding of the mode of action of receptor partial agonists and the receptor theory using a Full Logistic Model (FLM) of mixture toxicology. We describe the hypothesis that the effect of a partial agonist can be mathematically described via separation of agonistic and antagonistic behavior of the partial agonist where the antagonistic effect is described as an action of the compound producing zero effect. In this way, a competitive antagonist can be considered as an agonist with zero effect. This idea is also placed into a context with classical concepts, e.g., Gaddum's equation. Using the assumption that competitive antagonists are agonists with no effect, equations describing the microscopic and macroscopic equilibrium constants have been derived. Accordingly, we show that the constants could be calculated from the measured partial agonistic dose-response curve. As a consequence, we provide a simple mathematical tool for comparison of dose-response curves of drugs according to their affinities and efficacies.
What was Paul Ehrlich's role in the development of the receptor concept?
Ehrlich's side-chain-theory formed an important basis for his work on blood cells and on chemotherapy of infectious diseases such as sleeping-sickness and syphilis. In 1910, his research led to the introduction of Salvarsan, the famous ‘magic bullet’ against the germs of syphilis. Ehrlich's side-chain-theory was developed in the course of his studies into the staining of body cells and tissues, into the oxygen consumption of cells, and especially on the interaction between bacterial toxins and the so-called anti-toxins or antibodies formed by the body. In 1897 Ehrlich published for the first time a full account of his side-chain-theory of anti-toxin formation. The large ‘molecule’ of the cell protoplasm was supposed to have certain side-chains that were able to bind chemically the toxins produced by the bacteria. The thus occupied side-chains became unable to fulfil their usual functions in nutrition and oxygen consumption, forcing the cell to produce more side-chains. A surplus of side-chains was released into the blood stream where they bound as anti-toxins or antibodies to the bacterial toxins—forming thus the basis of immunity ( Figure 3 ). In 1900 Ehrlich replaced the term side-chain (or Seitenkette) with the term Receptor [11].
What are the receptors in a cell?
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?
Who are the pioneers in receptor function?
In recent years, the study of receptor function has taken full advantage of the molecular biology revolution, and many discoveries are being made that challenge the simple quantitative analyses introduced by pioneers such as Hill, Stephenson, Schild and others (which, it should be emphasised, were crucial in laying the foundations of the receptor concept in pharmacology).
What is the receptor concept?
The receptor concept is to pharmacology as homeostasis is to physiology, or metabolism to biochemistry. They provide the basic framework, and are the ‘Big Ideas' without which it is impossible to understand what the subjects are about. Try to imagine a pharmacology course that made no mention of receptors.
What did Clark and Gaddum find about competitive antagonism?
Both Clark and Gaddum described the now-familiar ‘parallel shift' of the log concentration–effect curve produced by a competitive antagonist . Clark's data covered an enormous 105-fold concentration range, rarely attempted by present-day pharmacologists. In retrospect, it is surprising that neither Hill nor Clark pursued the idea of competitive antagonism by deriving the very simple equations for the binding of two mutually exclusive compounds at the same population of sites. This was performed for the first time by Gaddum (1937)in a short communication to the Physiological Society. Clark was actually put off the idea of competitive antagonism for quite the wrong reason. He argued that recovery from atropine ought to be accelerated in the presence of acetylcholine if the two were acting at a common site, and found that it was not. So Clark concluded: “Atropine and acetylcholine, therefore, appear to be attached to different receptors in the heart cells, and their antagonism appears to be an antagonism of effects rather than of combination”. In fact, the simple competitive model does not predict the effect that Clark failed to see.
What is Clark's agonist/antagonist ratio?
Clark's [agonist] : [antagonist] ratio was actually a hair's breadth away from the agonist dose ratiometric, devised by Schild (see below); it was, however, a purely empirical metric, and a blind alley in relation to competitive antagonism. Clark was a very active founder member of the British Pharmacological Society. He died suddenly in 1941 at the age of 56, 5 years before the Society's journal came into being.
What were the two breakthroughs in the development of the receptor?
The second breakthrough was the direct measurement of drug binding, which led on to the isolation and cloning of receptors, revealing the biochemical reality of what had hitherto been an entirely abstract concept.
How did Paul Ehrlich come up with the idea of receptors?
His idea was that bacterial toxins combine with nutrient-capturing structures of cells (‘sidechains'), thus starving them. The cells respond by making more of these sidechains, some of which escape into the circulation as ‘antibodies' that combine with the toxin and make it harmless. He later suggested that the sidechains of bacteria differed from those of the host, and went on to study synthetic molecules, based on aniline dyes, that might act selectively on these bacterial sidechains, an endeavour that ended triumphantly with the discovery of Salvarsan in 1909, the first effective treatment for syphilis.
What is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism?
Chemical signalling is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism. Chemical recognition is the function of receptors, which, in addition to recognising endogenous chemical signals, are also the target of many important experimental and therapeutic drugs. Receptors, therefore, lie at the heart of pharmacology. This article describes the way in which the receptor concept originated early in the 20th century, and evolved through a highly innovative stage of quantitative theory based on chemical kinetics, to the point where receptors were first isolated and later cloned, until we now have a virtually complete catalogue of all the receptors present in the genome. Studies on signal transduction are revealing great complexity in the events linking ligand binding to the physiological or therapeutic response. Though some simple quantitative rules of ‘receptor theory' are still useful, the current emphasis is on unravelling the pathways that link receptors to responses, and it will be some time before we know enough about them to embark on the next phase of ‘receptor theory'.