Receptor antagonist

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Antagonists will block the binding of an agonist at a receptor molecule, inhibiting the signal produced by a receptor-agonist coupling. Antagonist 2.png
Antagonists will block the binding of an agonist at a receptor molecule, inhibiting the signal produced by a receptor–agonist coupling.

A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of receptor proteins. [1] They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, 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]

Contents

Etymology

The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, competitor, villain, enemy, rival", which is derived from anti- ("against") and agonizesthai ("to contend for a prize"). Antagonists were discovered in the 20th century by American biologist Bailey Edgren. [3] [4]

Receptors

Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. [5] Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site 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. [5] The activity of receptors can also be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. [6] 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. [7] 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. [7] [8] [9]

The term antagonist was originally coined to describe different profiles of drug effects. [10] The biochemical definition of a receptor antagonist was introduced by Ariens [11] and Stephenson [12] in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model. 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 that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.

Our understanding of the mechanism of drug-induced receptor activation and receptor theory 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. [13] The discovery of functional selectivity 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. [14] This means efficacy may actually depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug. [14]

Pharmacodynamics

Efficacy and potency

Agonists require higher dose/concentration to achieve the same effect when in the presence of a reversible competitive antagonist. Ligand response reversible competitive antagonist.svg
Agonists require higher dose/concentration to achieve the same effect when in the presence of a reversible competitive antagonist.

By definition, antagonists display no efficacy [12] 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, inverse agonists, and partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist. [5] The potency of an antagonist is usually defined by its half maximal inhibitory concentration (i.e., 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. [16] 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. [17]

Agonists get its maximum effect reduced when in the presence of an Irreversible Competitive Antagonist or a Reversible Non-Competitive Antagonist. Ligand response irreversible antagonist and noncompetitive.svg
Agonists get its maximum effect reduced when in the presence of an Irreversible Competitive Antagonist or a Reversible Non-Competitive Antagonist.

Affinity

The affinity of an antagonist for its binding site (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 that also block ion channels as well as antagonising agonist binding, cannot be analyzed using Schild regression. [18] [19] 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. [20] 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. [21] 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. [17]

Types

Competitive

Competitive antagonists bind to receptors at the same binding site (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. Sufficient concentrations of an antagonist will displace the agonist from the binding sites, resulting in a lower frequency of receptor activation. The level of activity of the receptor will be determined by the relative affinity of each molecule for the site and their relative concentrations. High concentrations of a competitive agonist will increase the proportion of receptors that the agonist occupies, higher concentrations of the antagonist will be required to obtain the same degree of binding site occupancy. [17] In functional assays using competitive antagonists, a parallel rightward shift of agonist dose–response curves with no alteration of the maximal response is observed. [23]

Competitive antagonists are used to prevent the activity of drugs, and to reverse the effects of drugs that have already been consumed. Naloxone (also known as Narcan) is used to reverse opioid overdose caused by drugs such as heroin or morphine. Similarly, Ro15-4513 is an antidote to alcohol and flumazenil is an antidote to benzodiazepines.

Competitive antagonists are sub-classified as reversible (surmountable) or irreversible (insurmountable) competitive antagonists, depending on how they interact with their receptor protein targets. [22] Reversible antagonists, which bind via noncovalent intermolecular forces, will eventually dissociate from the receptor, freeing the receptor to be bound again. [24] Irreversible antagonists bind via covalent intermolecular forces. Because there is not enough free energy to break covalent bonds in the local environment, the bond is essentially "permanent", meaning the receptor-antagonist complex will never dissociate. The receptor will thereby remain permanently antagonized until it is ubiquitinated and thus destroyed.

Non-competitive

A non-competitive antagonist is a type of insurmountable antagonist that may act in one of two ways: by binding to an allosteric site of the receptor, [25] [22] or by irreversibly binding to the active site of the receptor. The former meaning has been standardised by the IUPHAR, [22] and is equivalent to the antagonist being called an allosteric antagonist. [22] While the mechanism of antagonism is different in both of these phenomena, they are both called "non-competitive" because the end-results of each are functionally very similar. Unlike competitive antagonists, which affect the amount of agonist necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonist. This property earns them the name "non-competitive" because their effects cannot be negated, no matter how much agonist is present. 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. [23] The rightward shift will occur as a result of a receptor reserve (also known as spare receptors) [12] and inhibition of the agonist response will only occur when this reserve is depleted.

An antagonist that binds to the active site of a receptor is said to be "non-competitive" if the bond between the active site and the antagonist is irreversible or nearly so. [25] This usage of the term "non-competitive" may not be ideal, however, since the term "irreversible competitive antagonism" may also be used to describe the same phenomenon without the potential for confusion with the second meaning of "non-competitive antagonism" discussed below.

The second form of "non-competitive antagonists" act at an allosteric site. [25] These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site. They do not compete with agonists for binding at the active site. The bound antagonists may prevent conformational changes in the receptor required for receptor activation after the agonist binds. [26] Cyclothiazide has been shown to act as a reversible non-competitive antagonist of mGluR1 receptor. [27] Another example of a non-competitive is phenoxybenzamine which binds irreversibly (with covalent bonds) to alpha-adrenergic receptors, which in turn reduces the fraction of available receptors and reduces the maximal effect that can be produced by the agonist. [28]

Figure demonstrates the noncompetitive antagonistic behaviour of Phenoxybenzamine on alpha-adrenergiv norepinephrine receptors. Noncompetitive a-adrenergic agonistic action of Phenoxybenzamine.png
Figure demonstrates the noncompetitive antagonistic behaviour of Phenoxybenzamine on alpha-adrenergiv norepinephrine receptors.

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". [29] Memantine, used in the treatment of Alzheimer's disease, is an uncompetitive antagonist of the NMDA receptor. [30]

Silent antagonists

Chart demonstrating the difference between agonists, silent antagonists, and inverse agonists. Ligand response comparison.svg
Chart demonstrating the difference between agonists, silent antagonists, and inverse agonists.

Silent antagonists are competitive receptor antagonists that have zero intrinsic activity for activating a receptor. They are true antagonists, so to speak. The term was created to distinguish fully inactive antagonists from weak partial agonists or inverse agonists. [31]

Partial agonists

Partial agonists are defined as drugs that, at a given receptor, might differ in the amplitude of the functional response that they elicit after maximal receptor occupancy. Although they are agonists, partial agonists can act as a competitive antagonist in the presence of a full agonist, as it competes with the full agonist for receptor occupancy, thereby producing a net decrease in the receptor activation as compared to that observed with the full agonist alone. [32] [33] Clinically, their usefulness is derived from their ability to enhance deficient systems while simultaneously blocking excessive activity. Exposing a receptor to a high level of a partial agonist will ensure that it has a constant, weak level of activity, whether its normal agonist is present at high or low levels. In addition, it has been suggested that partial agonism prevents the adaptive regulatory mechanisms that frequently develop after repeated exposure to potent full agonists or antagonists. [34] [35] E.g. Buprenorphine, a partial agonist of the μ-opioid receptor, binds with weak morphine-like activity and is used clinically as an analgesic in pain management and as an alternative to methadone in the treatment of opioid dependence. [36]

Inverse agonists

An inverse agonist can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses. Constitutively active receptors that exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist but also inhibit the basal activity of the receptor. Many drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors. [37] [38] Antihistamines, originally classified as antagonists of histamine H1 receptors have been reclassified as inverse agonists. [39]

Reversibility

Many antagonists are reversible antagonists that, like most agonists, will bind and unbind a receptor at rates determined by receptor-ligand kinetics.

Irreversible antagonists covalently bind to the receptor target and, in general, cannot be removed; inactivating the receptor for the duration of the antagonist effects is determined by the rate of receptor turnover, the rate of synthesis of new receptors. Phenoxybenzamine is an example of an irreversible alpha blocker—it permanently binds to α adrenergic receptors, preventing adrenaline and noradrenaline from binding. [40] Inactivation of receptors normally results in a depression of the maximal response of agonist dose-response curves and a right shift in the curve occurs where there is a receptor reserve similar to non-competitive antagonists. A washout step in the assay will usually distinguish between non-competitive and irreversible antagonist drugs, as effects of non-competitive antagonists are reversible and activity of agonist will be restored. [23]

Irreversible competitive antagonists also involve competition between the agonist and antagonist of the receptor, but the rate of covalent bonding differs and depends on affinity and reactivity of the antagonist. [16] For some antagonists, there may be a distinct period during which they behave competitively (regardless of basal efficacy), and freely associate to and dissociate from the receptor, determined by receptor-ligand kinetics. But, once irreversible bonding has taken place, the receptor is deactivated and degraded. As for non-competitive antagonists and irreversible antagonists in functional assays with irreversible competitive antagonist drugs, there may be a shift in the log concentration–effect curve to the right, but, in general, both a decrease in slope and a reduced maximum are obtained. [16]

See also

Related Research Articles

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<span class="mw-page-title-main">Agonist</span> Chemical which binds to and activates a biochemical receptor

An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.

<span class="mw-page-title-main">Receptor (biochemistry)</span> Protein molecule receiving signals for a cell

In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and produce physiological responses such as change in the electrical activity of a cell. For example, GABA, an inhibitory neurotransmitter inhibits electrical activity of neurons by binding to GABAA receptors. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway.

<span class="mw-page-title-main">Pharmacodynamics</span> Area of Academic Study

Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms.

<span class="mw-page-title-main">Partial agonist</span> Agonist drug having partial efficacy at a receptor

In pharmacology, partial agonists are drugs that bind to 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, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone. Clinically, partial agonists can be used to activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present.

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

<span class="mw-page-title-main">Inverse agonist</span> Agent in biochemistry

In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−).

IC<sub>50</sub> Half maximal inhibitory concentration

Half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a particular inhibitory substance (e.g. drug) is needed to inhibit, in vitro, a given biological process or biological component by 50%. The biological component could be an enzyme, cell, cell receptor or microorganism. IC50 values are typically expressed as molar concentration.

<span class="mw-page-title-main">Ligand (biochemistry)</span> Substance that forms a complex with a biomolecule

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ligare, which means 'to bind'. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure.

<span class="mw-page-title-main">Schild equation</span>

In pharmacology, Schild regression analysis, based upon the Schild equation, both named for Heinz Otto Schild, are tools for studying the effects of agonists and antagonists on the response caused by the receptor or on ligand-receptor binding.

<span class="mw-page-title-main">Adrenergic antagonist</span>

An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.

Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept that receptors can mediate drug action at the beginning of the 20th century. Alfred Joseph Clark was the first to quantify drug-induced biological responses. So far, nearly all of the quantitative theoretical modelling of receptor function has centred on ligand-gated ion channels and G protein-coupled receptors.

<span class="mw-page-title-main">Agonist-antagonist</span>

In pharmacology the term agonist-antagonist or mixed agonist/antagonist is used to refer to a drug which under some conditions behaves as an agonist while under other conditions, behaves as an antagonist.

A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB1 receptor antagonists. The first CBR inverse agonist, rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists. Cannabidiol (CBD), a naturally occurring cannabinoid and a non-competitive CB1/CB2 receptor antagonist, as well as Δ9-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB1 ligand, that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant.

<span class="mw-page-title-main">Alazocine</span> Synthetic opioid analgesic

Alazocine, also known more commonly as N-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. In addition to its opioid activity, the drug is a sigma receptor agonist, and has been used widely in scientific research in studies of this receptor. Alazocine is described as a potent analgesic, psychotomimetic or hallucinogen, and opioid antagonist. Moreover, one of its enantiomers was the first compound that was found to selectively label the σ1 receptor, and led to the discovery and characterization of the receptor.

<span class="mw-page-title-main">Intrinsic activity</span> Measure of relative response to a drug

Intrinsic activity (IA) and efficacy refer to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its molecular target, and the EC50, which is a measure of the potency of the drug and which is proportional to both efficacy and affinity. This use of the word "efficacy" was introduced by Stephenson (1956) to describe the way in which agonists vary in the response they produce, even when they occupy the same number of receptors. High efficacy agonists can produce the maximal response of the receptor system while occupying a relatively low proportion of the receptors in that system. There is a distinction between efficacy and intrinsic activity.

In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcoholic beverages, function as psychoactive drugs. The site that an allosteric modulator binds to is not the same one to which an endogenous agonist of the receptor would bind. Modulators and agonists can both be called receptor ligands.

A receptor modulator, or receptor ligand, is a general term for a substance, endogenous or exogenous, that binds to and regulates the activity of chemical receptors. They are ligands that can act on different parts of receptors and regulate activity in a positive, negative, or neutral direction with varying degrees of efficacy. Categories of these modulators include receptor agonists and receptor antagonists, as well as receptor partial agonists, inverse agonists, orthosteric modulators, and allosteric modulators, Examples of receptor modulators in modern medicine include CFTR modulators, selective androgen receptor modulators (SARMs), and muscarinic ACh receptor modulators.

<span class="mw-page-title-main">Methoctramine</span> Chemical compound

Methoctramine is a polymethylene tetraamine that acts as a muscarinic antagonist. It preferentially binds to the pre-synaptic receptor M2, a muscarinic acetylcholine ganglionic protein complex present basically in heart cells. In normal conditions -absence of methoctramine-, the activation of M2 receptors diminishes the speed of conduction of the sinoatrial and atrioventricular nodes thus reducing the heart rate. Thanks to its apparently high cardioselectivity, it has been studied as a potential parasymphatolitic drug, particularly against bradycardia. However, currently it is only addressed for research purposes, since the administration to humans is still unavailable.

References

  1. ↑ "Pharmacology Guide: In vitro pharmacology: concentration-response curves." GlaxoWellcome. Retrieved on December 6, 2007.
  2. ↑ Hopkins AL, Groom CR (September 2002). "The druggable genome". Nature Reviews. Drug Discovery. 1 (9): 727–30. doi:10.1038/nrd892. PMID   12209152. S2CID   13166282.
  3. ↑ "Antagonist". Online Etymology Dictionary. Retrieved 28 November 2010.
  4. ↑ "antagonist" . Oxford English Dictionary (Online ed.). Oxford University Press.(Subscription or participating institution membership required.)
  5. 1 2 3 T. Kenakin (2006) A Pharmacology Primer: Theory, Applications, and Methods. 2nd Edition Elsevier ISBN   0-12-370599-1
  6. ↑ May LT, Avlani VA, Sexton PM, Christopoulos A (2004). "Allosteric modulation of G protein-coupled receptors". Current Pharmaceutical Design. 10 (17): 2003–13. doi:10.2174/1381612043384303. PMID   15279541. S2CID   36602982.
  7. 1 2 Christopoulos A (March 2002). "Allosteric binding sites on cell-surface receptors: novel targets for drug discovery". Nature Reviews. Drug Discovery. 1 (3): 198–210. doi:10.1038/nrd746. PMID   12120504. S2CID   13230838.
  8. ↑ Bleicher KH, Green LG, Martin RE, Rogers-Evans M (June 2004). "Ligand identification for G-protein-coupled receptors: a lead generation perspective". Current Opinion in Chemical Biology. 8 (3): 287–96. doi:10.1016/j.cbpa.2004.04.008. PMID   15183327.
  9. ↑ Rees S, Morrow D, Kenakin T (2002). "GPCR drug discovery through the exploitation of allosteric drug binding sites". Receptors & Channels. 8 (5–6): 261–8. doi:10.1080/10606820214640. PMID   12690954.
  10. ↑ Negus SS (June 2006). "Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists". Biochemical Pharmacology. 71 (12): 1663–70. doi:10.1016/j.bcp.2005.12.038. PMC   1866283 . PMID   16460689.
  11. ↑ Ariens EJ (September 1954). "Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory". Archives Internationales de Pharmacodynamie et de Thérapie. 99 (1): 32–49. PMID   13229418.
  12. 1 2 3 Stephenson RP (February 1997). "A modification of receptor theory. 1956". British Journal of Pharmacology. 120 (4 Suppl): 106–20, discussion 103–5. doi:10.1111/j.1476-5381.1997.tb06784.x. PMC   3224279 . PMID   9142399. of the original article.
  13. ↑ Vauquelin G, Van Liefde I (February 2005). "G protein-coupled receptors: a count of 1001 conformations". Fundamental & Clinical Pharmacology. 19 (1): 45–56. doi: 10.1111/j.1472-8206.2005.00319.x . PMID   15660959. S2CID   609867.
  14. 1 2 Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (January 2007). "Functional selectivity and classical concepts of quantitative pharmacology". The Journal of Pharmacology and Experimental Therapeutics. 320 (1): 1–13. doi:10.1124/jpet.106.104463. PMID   16803859. S2CID   447937.
  15. 1 2 3 Ritter J, Flower R, Henderson G, Loke YK, MacEwan D, Rang H (2020). Rang and Dale's pharmacology (9 ed.). Edinburgh: Elsevier. ISBN   978-0-7020-8060-9. OCLC   1081403059.
  16. 1 2 3 Lees P, Cunningham FM, Elliott J (December 2004). "Principles of pharmacodynamics and their applications in veterinary pharmacology". Journal of Veterinary Pharmacology and Therapeutics. 27 (6): 397–414. doi:10.1111/j.1365-2885.2004.00620.x. PMID   15601436.
  17. 1 2 3 Swinney DC (September 2004). "Biochemical mechanisms of drug action: what does it take for success?". Nature Reviews. Drug Discovery. 3 (9): 801–8. doi:10.1038/nrd1500. PMID   15340390. S2CID   28668800.
  18. ↑ Wyllie DJ, Chen PE (March 2007). "Taking the time to study competitive antagonism". British Journal of Pharmacology. 150 (5): 541–51. doi:10.1038/sj.bjp.0706997. PMC   2189774 . PMID   17245371.
  19. ↑ Colquhoun D (December 2007). "Why the Schild method is better than Schild realised". Trends in Pharmacological Sciences. 28 (12): 608–14. doi:10.1016/j.tips.2007.09.011. PMID   18023486.
  20. ↑ Schild HO (February 1975). "An ambiguity in receptor theory". British Journal of Pharmacology. 53 (2): 311. doi:10.1111/j.1476-5381.1975.tb07365.x. PMC   1666289 . PMID   1148491.
  21. ↑ Cheng Y, Prusoff WH (December 1973). "Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction". Biochemical Pharmacology. 22 (23): 3099–108. doi:10.1016/0006-2952(73)90196-2. PMID   4202581.
  22. 1 2 3 4 5 Neubig RR, Spedding M, Kenakin T, Christopoulos A (December 2003). "International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology" (PDF). Pharmacological Reviews. 55 (4): 597–606. doi:10.1124/pr.55.4.4. PMID   14657418. S2CID   1729572.
  23. 1 2 3 Vauquelin G, Van Liefde I, Birzbier BB, Vanderheyden PM (August 2002). "New insights in insurmountable antagonism". Fundamental & Clinical Pharmacology. 16 (4): 263–72. doi:10.1046/j.1472-8206.2002.00095.x. PMID   12570014. S2CID   6145796.
  24. ↑ Stevens, E. (2013) Medicinal Chemistry: The Modern Drug Discovery Process. pg. 79, 84
  25. 1 2 3 eds, David E. Golan, ed.-in-chief ; Armen H. Tashjian Jr., deputy ed. ; Ehrin J. Armstrong, April W. Armstrong, associate (2008). Principles of pharmacology: the pathophysiologic basis of drug therapy (2nd ed.). Philadelphia, Pa., [etc.]: Lippincott Williams & Wilkins. p. 25. ISBN   978-0-7817-8355-2 . Retrieved 2012-02-05.{{cite book}}: CS1 maint: multiple names: authors list (link)
  26. ↑ D.E. Golan, A.H Tashjian Jr, E.J. Armstrong, A.W. Armstrong. (2007) Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Lippincott Williams & Wilkins ISBN   0-7817-8355-0
  27. ↑ Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT (March 2007). "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists". Neuropharmacology. 52 (3): 744–54. doi:10.1016/j.neuropharm.2006.09.018. PMC   1876747 . PMID   17095021.
  28. 1 2 "basic_principles_of_pharm [TUSOM | Pharmwiki]". tmedweb.tulane.edu. Retrieved 2023-07-21.
  29. ↑ Lipton SA (January 2004). "Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults". NeuroRx. 1 (1): 101–10. doi:10.1602/neurorx.1.1.101. PMC   534915 . PMID   15717010.
  30. ↑ Parsons CG, Stöffler A, Danysz W (November 2007). "Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse". Neuropharmacology. 53 (6): 699–723. doi:10.1016/j.neuropharm.2007.07.013. PMID   17904591. S2CID   6599658.
  31. ↑ Fletcher A, Cliffe IA, Dourish CT (December 1993). "Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents". Trends in Pharmacological Sciences. 14 (12): 41–48. doi:10.1016/0165-6147(93)90185-m. PMID   8122313. S2CID   4274320.
  32. ↑ Principles and Practice of Pharmacology for Anaesthetists By Norton Elwy Williams, Thomas Norman Calvey Published 2001 Blackwell Publishing ISBN   0-632-05605-3
  33. ↑ Patil PN (2002). "Everhardus J. Ariëns (1918–2002): a tribute". Trends in Pharmacological Sciences. 23 (7): 344–5. doi:10.1016/S0165-6147(02)02068-0.
  34. ↑ Bosier B, Hermans E (August 2007). "Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance". Trends in Pharmacological Sciences. 28 (8): 438–46. doi:10.1016/j.tips.2007.06.001. PMID   17629964.
  35. ↑ Pulvirenti L, Koob GF (April 2002). "Being partial to psychostimulant addiction therapy". Trends in Pharmacological Sciences. 23 (4): 151–3. doi:10.1016/S0165-6147(00)01991-X. PMID   11931978.
  36. ↑ Vadivelu N, Hines RL (2007). "Buprenorphine: a unique opioid with broad clinical applications". Journal of Opioid Management. 3 (1): 49–58. doi: 10.5055/jom.2007.0038 . PMID   17367094.
  37. ↑ Greasley PJ, Clapham JC (December 2006). "Inverse agonism or neutral antagonism at G-protein coupled receptors: a medicinal chemistry challenge worth pursuing?". European Journal of Pharmacology. 553 (1–3): 1–9. doi:10.1016/j.ejphar.2006.09.032. PMID   17081515.
  38. ↑ Kenakin T (January 2004). "Efficacy as a vector: the relative prevalence and paucity of inverse agonism". Molecular Pharmacology. 65 (1): 2–11. doi:10.1124/mol.65.1.2. PMID   14722230. S2CID   115140.
  39. ↑ Leurs R, Church MK, Taglialatela M (April 2002). "H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects". Clinical and Experimental Allergy. 32 (4): 489–98. doi:10.1046/j.0954-7894.2002.01314.x. PMID   11972592. S2CID   11849647.
  40. ↑ Frang H, Cockcroft V, Karskela T, Scheinin M, Marjamäki A (August 2001). "Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors". The Journal of Biological Chemistry. 276 (33): 31279–84. doi: 10.1074/jbc.M104167200 . PMID   11395517.

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