A receptor antagonist is a type of receptor In biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signaling molecules may attach. A molecule which binds to a receptor is called a ligand, and may be a peptide (short protein) or other small molecule, such as a neurotransmitter, a hormone, a ligand In biochemistry and pharmacology, a ligand is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein or drug A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage that does not provoke a biological response itself upon binding to a receptor In biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signaling molecules may attach. A molecule which binds to a receptor is called a ligand, and may be a peptide (short protein) or other small molecule, such as a neurotransmitter, a hormone, a, but blocks or dampens agonist An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist-mediated responses.[1] In pharmacology Pharmacology is the branch of biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals. The field encompasses drug, antagonists have affinity In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into its component ions. The dissociation constant is but no efficacy In a healthcare context, efficacy indicates the capacity for beneficial change of a given intervention (e.g. a medicine, medical device, surgical procedure, or a public health intervention) for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist or inverse agonist In pharmacology, an inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors. Inverse agonists exert the opposite pharmacological effect of a receptor agonist. Inverse agonists are effective against certain types of receptors that have intrinsic at receptors. Antagonists mediate their effects by binding to the active site or to allosteric sites on receptors, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally-defined binding sites on receptors.[2]
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Receptors
Main article: Receptor (biochemistry) In biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signaling molecules may attach. A molecule which binds to a receptor is called a ligand, and may be a peptide (short protein) or other small molecule, such as a neurotransmitter, a hormone, aBiochemical receptors In biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or the cytoplasm of a cell, to which one or more specific kinds of signaling molecules may attach. A molecule which binds to a receptor is called a ligand, and may be a peptide (short protein) or other small molecule, such as a neurotransmitter, a hormone, a are large protein Proteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. The sequence of amino acids in a protein is defined by the sequence of a gene, which is encoded molecules that can be activated by the binding of a ligand In biochemistry and pharmacology, a ligand is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein (such as a hormone A hormone is a chemical released by a cell in one part of the body, that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. It is essentially a chemical messenger that transports a signal from one cell to another. All multicellular organisms produce hormones; or drug A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage).[3] Receptors can be membrane-bound, occurring on the cell membrane of cells, or intracellular, such as on the nucleus In cell biology, the nucleus , also sometimes referred to as the "control center", is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes or mitochondrion In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 10 micrometers (μm) in diameter. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of. Binding occurs as a result of noncovalent interaction between the receptor and its ligand, at locations called the binding site In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands, or more specifically, protein ligands—form a chemical bond on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly.[3] The activity of receptors can also be regulated In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors. The term allostery by the binding of a ligand to other sites on the receptor, as in allosteric binding sites.[4] Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the active site or the allosteric site.[5] In addition, antagonists may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity to exert their effects.[5][6][7]
The term antagonist was originally coined to describe different profiles of drug effects.[8] The biochemical definition of a receptor antagonist was introduced by Ariens[9] and Stephenson[10] in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model Receptor theory is the application of receptor models to explain drug behaviour. 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. A J Clark was the first to quantify. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by 'blocking' the receptor from the agonist. This definition also remains in use for physiological antagonists, substances which have opposing physiological actions, but act at different receptors. For example, histamine Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective lowers arterial pressure through vasodilation Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When vessels dilate, the flow of blood is increased at the histamine H1 receptor The H1 receptor is a histamine receptor belonging to the family of G-protein-coupled receptors. This receptor which is activated by the biogenic amine histamine is expressed throughout the body, specifically in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. The H1 receptor is linked to an, while adrenaline Epinephrine is a hormone and neurotransmitter.. It increases heart rate, contracts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. Chemically, epinephrine is a catecholamine, a monoamine produced only by the adrenal glands from the amino acids phenylalanine and tyrosine raises arterial pressure through vasoconstriction mediated by β-adrenergic receptor activation.
Our understanding of the mechanism of drug induced receptor activation and receptor theory Receptor theory is the application of receptor models to explain drug behaviour. 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. A J Clark was the first to quantify and the biochemical definition of a receptor antagonist continues to evolve. The two state model of receptor activation has given way to multistate models with intermediate conformational states.[11] The discovery of functional selectivity Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others.[12] This means efficacy may actually depend on where that receptor is expressed, altering the view that efficacy In a healthcare context, efficacy indicates the capacity for beneficial change of a given intervention (e.g. a medicine, medical device, surgical procedure, or a public health intervention) at a receptor is receptor-independent property of a drug.[12]
Pharmacodynamics
Main article: Pharmacodynamics Pharmacodynamics is the study of the physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect. One dominant example is drug-receptor interactions as modeled byEfficacy and potency
By definition, antagonists display no efficacy In a healthcare context, efficacy indicates the capacity for beneficial change of a given intervention (e.g. a medicine, medical device, surgical procedure, or a public health intervention)[10] to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, however, antagonists inhibit the function of agonists An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist, inverse agonists In pharmacology, an inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors. Inverse agonists exert the opposite pharmacological effect of a receptor agonist. Inverse agonists are effective against certain types of receptors that have intrinsic and partial agonists An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist. In functional antagonist assays, a dose-response curve The dose-response relationship, or exposure-response relationship, describes the change in effect on an organism caused by differing levels of exposure to a stressor (usually a chemical) after a certain exposure time. This may apply to individuals (eg: a small amount has no observable effect, a large amount is fatal), or to populations (eg: how measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist.[3] The potency of an antagonist is usually defined by its IC50 value. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC50 value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar.[13] The lower the IC50, the greater the potency of the antagonist, and the lower the concentration of drug that is required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects.[14]
Affinity
The affinity of an antagonist for its binding site In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands, or more specifically, protein ligands—form a chemical bond (Ki), i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and Ki determination is independent of the affinity, efficacy or concentration of the agonist used. However, it is important that equilibrium has been reached. The effects of receptor desensitization on reaching equilibrium must also be taken into account. The affinity constant of antagonists exhibiting two or more effects, such as in competitive neuromuscular-blocking agents which also block ion channels as well as antagonising agonist binding, cannot be analyzed using Schild regression.[15][16] Schild regression involves comparing the change in the dose ratio, the ratio of the EC50 of an agonist alone compared to the EC50 in the presence of a competitive antagonist as determined on a dose response curve. Altering the amount of antagonist used in the assay can alter the dose ratio. In Schild regression, a plot is made of the log(dose ratio-1) versus the log concentration of antagonist for a range of antagonist concentrations.[17] The affinity or Ki is where the line cuts the x-axis on the regression plot. Whereas, with Schild regression, antagonist concentration is varied in experiments used to derive Ki values from the Cheng-Prusoff equation, agonist concentrations are varied. Affinity for competitive agonists and antagonists is related by the Cheng-Prusoff factor used to calculate the Ki (affinity constant for an antagonist) from the shift in IC50 that occurs during competitive inhibition.[18] The Cheng-Prusoff factor takes into account the effect of altering agonist concentration and agonist affinity for the receptor on inhibition produced by competitive antagonists.[14]
Types
Competitive
Competitive antagonists A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor. Sufficient antagonist will displace the agonist from the binding sites, resulting in a lower frequency of receptor activation (also known as surmountable antagonists) reversibly bind to receptors at the same binding site In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands, or more specifically, protein ligands—form a chemical bond (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists "compete" for the same binding site on the receptor. Once bound, an antagonist will block agonist binding. The level of activity of the receptor will be determined by the relative affinity In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into its component ions. The dissociation constant is of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist will increase the proportion of receptors which the agonist occupies, higher concentrations of the antagonist will be required to obtain the same degree of binding site occupancy.[14] In functional assays using competitive antagonists, a parallel rightward shifts of agonist dose–response curves with no alteration of the maximal response is observed.[19] The interleukin-1 Interleukin-1 is one of the first cytokines ever described[citation needed]. Its initial discovery was as a factor that could induce fever, control lymphocytes, increase the number of bone marrow cells and cause degeneration of bone joints[citation needed]. At this time, IL-1 was known under several other names including endogenous pyrogen, receptor antagonist, IL-1Ra is an example of a competitive antagonist.[20] The effects of a competitive antagonist may be overcome by increasing the concentration of agonist. Often (though not always) these antagonists possess a very similar chemical structure to that of the agonist.
Non-competitive
Non-competitive antagonists (non-surmountable) are also known as allosteric In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors. The term allostery antagonists. These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. Cyclothiazide has been shown to act as a reversible non-competitive antagonist of mGluR1 receptor.[21] Thus, they do not compete with agonists for binding. The bound antagonists may result in a decreased affinity of an agonist for that receptor, or alternatively may prevent conformational changes in the receptor required for receptor activation after the agonist binds.[22] No amount of agonist can completely overcome the inhibition once it has been established. In functional assays of non-competitive antagonists, depression of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced.[19] The rightward shift will occur as a result of a receptor reserve[10] and inhibition of the agonist response will only occur when this reserve is depleted.
Uncompetitive
Uncompetitive antagonists differ from non-competitive antagonists in that they require receptor activation by an agonist before they can bind to a separate allosteric binding site. This type of antagonism produces a kinetic profile in which "the same amount of antagonist blocks higher concentrations of agonist better than lower concentrations of agonist".[23] Memantine EU EMA:Link, US FDA:link, used in the treatment of Alzheimer's disease Alzheimer's disease , also called Alzheimer disease, Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Generally, it is diagnosed, is an uncompetitive antagonist of the NMDA receptor The NMDAR is a specific type of ionotropic glutamate receptor. NMDA is the name of a selective agonist that binds to NMDA receptors but not to other glutamate receptors. Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. A unique property of the NMDA receptor is its voltage-dependent activation,.[24]
Silent antagonists
Silent antagonists are competitive receptor antagonists that have zero intrinsic activity In a healthcare context, efficacy indicates the capacity for beneficial change of a given intervention (e.g. a medicine, medical device, surgical procedure, or a public health intervention) for activating a receptor. They are true antagonists, so to speak. The term was created to distinguish fully inactive antagonists from weak partial agonists Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic effects - when both a full agonist and partial agonist are present, the partial agonist actually acts as a competitive antagonist, or inverse agonists In pharmacology, an inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors. Inverse agonists exert the opposite pharmacological effect of a receptor agonist. Inverse agonists are effective against certain types of receptors that have intrinsic.
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