Editing Receptor antagonist

{{Short description|Type of receptor ligand or drug that blocks a biological response}}
[[File:Antagonist 2.png|thumb|Antagonists will block the binding of an [[agonist]] at a [[Receptor (biochemistry)|receptor]] molecule, inhibiting the signal produced by a receptor–agonist coupling.]]

A '''receptor antagonist''' is a type of  [[Receptor (biochemistry)|receptor]] [[ligand (biochemistry)|ligand]] or [[drug]] that blocks or dampens a biological response by binding to and blocking a [[Receptor (biochemistry)|receptor]] rather than activating it like an [[agonist]]. Antagonist drugs interfere in the natural operation of receptor proteins.<ref name="pharmguide">"[http://www.pdg.cnb.uam.es/cursos/Barcelona2002/pages/Farmac/Comput_Lab/Guia_Glaxo/chap2c.html Pharmacology Guide: In vitro pharmacology: concentration-response curves] {{Webarchive|url=https://web.archive.org/web/20190726074523/http://www.pdg.cnb.uam.es/cursos/Barcelona2002/pages/Farmac/Comput_Lab/Guia_Glaxo/chap2c.html |date=2019-07-26 }}." ''[[GlaxoSmithKline|GlaxoWellcome]].'' Retrieved on December 6, 2007.</ref> They are sometimes called '''blockers'''; examples include [[alpha blocker]]s, [[beta blocker]]s, and [[calcium channel blocker]]s. In [[pharmacology]], '''antagonists''' have [[Binding affinity|affinity]] but no [[efficacy#Pharmacology|efficacy]] for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an <!--competitive-->[[agonist]] or [[inverse agonist]] at receptors. Antagonists mediate their effects by binding to the [[active site]] or to the [[allosteric regulation|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.<ref name="pmid12209152">{{cite journal | vauthors = Hopkins AL, Groom CR | title = The druggable genome | journal = Nature Reviews. Drug Discovery | volume = 1 | issue = 9 | pages = 727–30 | date = September 2002 | pmid = 12209152 | doi = 10.1038/nrd892 | s2cid = 13166282 }}</ref>

==Etymology==
The English word antagonist in pharmaceutical terms comes from the [[Greek language|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.<ref>{{cite web |url=http://www.etymonline.com/index.php?search=antagonist&searchmode=none |title=Antagonist |publisher=Online Etymology Dictionary |access-date=28 November 2010}}</ref><ref>{{OED|antagonist}}</ref>

==Receptors==
{{Main|Receptor (biochemistry)}}

Biochemical [[Receptor (biochemistry)|receptor]]s are large [[protein]] molecules that can be activated by the binding of a [[Ligand (biochemistry)|ligand]] such as a [[hormone]] or a [[drug]].<ref name="2006Kenakin">T. Kenakin (2006) A Pharmacology Primer: Theory, Applications, and Methods. 2nd Edition Elsevier {{ISBN|0-12-370599-1}}</ref> Receptors can be membrane-bound, as [[cell surface receptor]]s, or inside the cell as [[intracellular receptor]]s, such as [[nuclear receptor]]s 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.<ref name="2006Kenakin"/> The activity of receptors can also be [[allosteric regulation|regulated]] by the binding of a ligand to other sites on the receptor, as in [[Allosteric regulation|allosteric binding sites]].<ref>{{cite journal | vauthors = May LT, Avlani VA, Sexton PM, Christopoulos A | title = Allosteric modulation of G protein-coupled receptors | journal = Current Pharmaceutical Design | volume = 10 | issue = 17 | pages = 2003–13 | year = 2004 | pmid = 15279541 | doi = 10.2174/1381612043384303 | s2cid = 36602982 }}</ref> 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.<ref name="Christopoulos">{{cite journal | vauthors = Christopoulos A | title = Allosteric binding sites on cell-surface receptors: novel targets for drug discovery | journal = Nature Reviews. Drug Discovery | volume = 1 | issue = 3 | pages = 198–210 | date = March 2002 | pmid = 12120504 | doi = 10.1038/nrd746 | s2cid = 13230838 }}</ref> 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.<ref name="Christopoulos"/><ref>{{cite journal | vauthors = Bleicher KH, Green LG, Martin RE, Rogers-Evans M | title = Ligand identification for G-protein-coupled receptors: a lead generation perspective | journal = Current Opinion in Chemical Biology | volume = 8 | issue = 3 | pages = 287–96 | date = June 2004 | pmid = 15183327 | doi = 10.1016/j.cbpa.2004.04.008 }}</ref><ref>{{cite journal | vauthors = Rees S, Morrow D, Kenakin T | title = GPCR drug discovery through the exploitation of allosteric drug binding sites | journal = Receptors & Channels | volume = 8 | issue = 5–6 | pages = 261–8 | year = 2002 | pmid = 12690954 | doi = 10.1080/10606820214640 }}</ref>

The term ''antagonist'' was originally coined to describe different profiles of drug effects.<ref>{{cite journal | vauthors = Negus SS | title = Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists | journal = Biochemical Pharmacology | volume = 71 | issue = 12 | pages = 1663–70 | date = June 2006 | pmid = 16460689 | pmc = 1866283 | doi = 10.1016/j.bcp.2005.12.038 }}</ref> The biochemical definition of a receptor antagonist was introduced by Ariens<ref>{{cite journal | vauthors = Ariens EJ | title = Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory | journal = Archives Internationales de Pharmacodynamie et de Thérapie | volume = 99 | issue = 1 | pages = 32–49 | date = September 1954 | pmid = 13229418 }}</ref> and Stephenson<ref name=stephanson>{{cite journal | vauthors = Stephenson RP | title = A modification of receptor theory. 1956 | journal = British Journal of Pharmacology | volume = 120 | issue = 4 Suppl | pages = 106–20; discussion 103–5 | date = February 1997 | pmid = 9142399 | pmc = 3224279 | doi = 10.1111/j.1476-5381.1997.tb06784.x }} of the original article.</ref> in the 1950s. The current accepted definition of receptor antagonist is based on the [[Receptor theory#Nature of Receptor-Drug interactions|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|histamine H<sub>1</sub> receptor]], while [[adrenaline]] raises arterial pressure through vasoconstriction mediated by alpha[[Alpha adrenergic receptor|-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.<ref>{{cite journal | vauthors = Vauquelin G, Van Liefde I | title = G protein-coupled receptors: a count of 1001 conformations | journal = Fundamental & Clinical Pharmacology | volume = 19 | issue = 1 | pages = 45–56 | date = February 2005 | pmid = 15660959 | doi = 10.1111/j.1472-8206.2005.00319.x | s2cid = 609867 | doi-access = free }}</ref> The discovery of [[Functional Selectivity|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.<ref name="Urban2007">{{cite journal|author8-link=Bryan Roth | vauthors = 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 | title = Functional selectivity and classical concepts of quantitative pharmacology | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 320 | issue = 1 | pages = 1–13 | date = January 2007 | pmid = 16803859 | doi = 10.1124/jpet.106.104463 | s2cid = 447937 | url = https://cdr.lib.unc.edu/concern/articles/xs55mf307 }}</ref>  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.<ref name=Urban2007/>

==Pharmacodynamics==
{{Main|Pharmacodynamics}}

===Efficacy and potency===
[[File:Ligand response reversible competitive antagonist.svg|thumb|Agonists require higher dose/concentration to achieve the same effect when in the presence of a reversible competitive antagonist.<ref name="Rang2020">{{Cite book |vauthors=Ritter J, Flower R, Henderson G, Loke YK, MacEwan D, Rang H |title=Rang and Dale's pharmacology |publisher=Elsevier |year=2020 |isbn=978-0-7020-8060-9 |edition=9 |location=Edinburgh |language=en |oclc=1081403059}}</ref>]]
By definition, antagonists display no [[efficacy]]<ref name=stephanson/> to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, however, antagonists inhibit the function of [[agonist]]s, [[inverse agonist]]s, and [[Agonist|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.<ref name="2006Kenakin"/> The [[Potency (pharmacology)|potency]] of an antagonist is usually defined by its ''half maximal inhibitory concentration'' (i.e., [[IC50|IC<sub>50</sub>]] 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 IC<sub>50</sub> 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.<ref name="Lees2004">{{cite journal | vauthors = Lees P, Cunningham FM, Elliott J | title = Principles of pharmacodynamics and their applications in veterinary pharmacology | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 27 | issue = 6 | pages = 397–414 | date = December 2004 | pmid = 15601436 | doi = 10.1111/j.1365-2885.2004.00620.x | url = http://researchonline.rvc.ac.uk/id/eprint/912/ }}</ref> The lower the IC<sub>50</sub> 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.<ref name="Swinney2004">{{cite journal | vauthors = Swinney DC | title = Biochemical mechanisms of drug action: what does it take for success? | journal = Nature Reviews. Drug Discovery | volume = 3 | issue = 9 | pages = 801–8 | date = September 2004 | pmid = 15340390 | doi = 10.1038/nrd1500 | s2cid = 28668800 }}</ref>
[[File:Ligand response irreversible antagonist and noncompetitive.svg|thumb|Agonists get its maximum effect reduced when in the presence of an Irreversible Competitive Antagonist or a Reversible Non-Competitive Antagonist.<ref name="Rang2020" />]]

===Affinity===
The affinity of an antagonist for its [[binding site]] (K<sub>i</sub>), 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 K<sub>i</sub> 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.<ref>{{cite journal | vauthors = Wyllie DJ, Chen PE | title = Taking the time to study competitive antagonism | journal = British Journal of Pharmacology | volume = 150 | issue = 5 | pages = 541–51 | date = March 2007 | pmid = 17245371 | pmc = 2189774 | doi = 10.1038/sj.bjp.0706997 }}</ref><ref>{{cite journal | vauthors = Colquhoun D | title = Why the Schild method is better than Schild realised | journal = Trends in Pharmacological Sciences| volume = 28 | issue = 12 | pages = 608–14 | date = December 2007 | pmid = 18023486 | doi = 10.1016/j.tips.2007.09.011 }}</ref> Schild regression involves comparing the change in the dose ratio, the ratio of the EC<sub>50</sub> of an agonist alone compared to the [[EC50|EC<sub>50</sub>]] 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 equation|Schild regression]], a plot is made of the log (dose ratio-1) versus the log concentration of antagonist for a range of antagonist concentrations.<ref>{{cite journal | vauthors = Schild HO | title = An ambiguity in receptor theory | journal = British Journal of Pharmacology | volume = 53 | issue = 2 | page = 311 | date = February 1975 | pmid = 1148491 | pmc = 1666289 | doi = 10.1111/j.1476-5381.1975.tb07365.x }}</ref> The affinity or K<sub>i</sub> 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 K<sub>i</sub> 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 K<sub>i</sub> (affinity constant for an antagonist) from the shift in IC<sub>50</sub> that occurs during [[competitive inhibition]].<ref>{{cite journal | vauthors = Cheng Y, Prusoff WH | title = Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction | journal = Biochemical Pharmacology | volume = 22 | issue = 23 | pages = 3099–108 | date = December 1973 | pmid = 4202581 | doi = 10.1016/0006-2952(73)90196-2 }}</ref> 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.<ref name="Swinney2004"/>

==Types==
{{See also|Enzyme_inhibitor#Types_of_reversible_inhibitors|label 1=Enzyme inhibitor § Types of reversible inhibitors}}

===Competitive===
{{Further|Competitive inhibition}}

{{expand section|information about irreversible/insurmountable competitive antagonists<ref name="IUPHAR: Pharmacology terms and symbols" />|date=November 2017|small=no}}
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 (pharmacology)|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.<ref name="Swinney2004"/> In functional assays using competitive antagonists, a parallel rightward shift of agonist dose–response curves with no alteration of the maximal response is observed.<ref name="Vauquelin2002">{{cite journal | vauthors = Vauquelin G, Van Liefde I, Birzbier BB, Vanderheyden PM | title = New insights in insurmountable antagonism | journal = Fundamental & Clinical Pharmacology | volume = 16 | issue = 4 | pages = 263–72 | date = August 2002 | pmid = 12570014 | doi = 10.1046/j.1472-8206.2002.00095.x | s2cid = 6145796 }}</ref>

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 [[ethanol|alcohol]] and [[flumazenil]] is an antidote to [[benzodiazepine]]s.

Competitive antagonists are sub-classified as [[#Reversibility|reversible]] (''surmountable'') or [[#Reversibility|irreversible]] (''insurmountable'') competitive antagonists, depending on how they interact with their [[Receptor (biochemistry)|receptor protein]] targets.<ref name="IUPHAR: Pharmacology terms and symbols">{{cite journal | vauthors = Neubig RR, Spedding M, Kenakin T, Christopoulos A | title = International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology | journal = Pharmacological Reviews | volume = 55 | issue = 4 | pages = 597–606 | date = December 2003 | pmid = 14657418 | doi = 10.1124/pr.55.4.4 | s2cid = 1729572 | url = http://www.guidetopharmacology.org/pdfs/termsAndSymbols.pdf }}</ref> Reversible antagonists, which bind via noncovalent intermolecular forces, will eventually dissociate from the receptor, freeing the receptor to be bound again.<ref>Stevens, E. (2013) Medicinal Chemistry: The Modern Drug Discovery Process. pg. 79, 84</ref> Irreversible antagonists bind via covalent intermolecular forces.<ref>{{Cite journal |date=2010-06-03 |title=Strategies for Discovering and Derisking Covalent, Irreversible Enzyme Inhibitors |journal=Future Medicinal Chemistry |language=en |volume=2 |issue=6 |pages=949–964 |doi=10.4155/fmc.10.21 |issn=1756-8919 |last1=Johnson |first1=Douglas S. |last2=Weerapana |first2=Eranthie |last3=Cravatt |first3=Benjamin F. |pmid=20640225 |pmc=2904065 }}</ref> Because there is not enough [[thermodynamic free energy|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 [[ubiquitin]]ated 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,<ref name=Golan25>{{cite book|last=eds|first=David E. Golan, ed.-in-chief; Armen H. Tashjian Jr., deputy ed.; Ehrin J. Armstrong, April W. Armstrong, associate|title=Principles of pharmacology: the pathophysiologic basis of drug therapy|year=2008|publisher=Lippincott Williams & Wilkins|location=Philadelphia, Pa., [etc.]|isbn=978-0-7817-8355-2|page=25|edition=2nd|url=https://books.google.com/books?id=az8uSDkB0mgC&q=noncompetitive+active+site+antagonist&pg=PA23|access-date=2012-02-05}}</ref><ref name="IUPHAR: Pharmacology terms and symbols" /> or by irreversibly binding to the active site of the receptor.<!-- This is actually cited on source 21, though admittedly a bit vague. "In contrast, some antagonists, when in close enough proximity to their binding site, may form a stable covalent bond with it (irreversible competitive antagonism), and the antagonism becomes insurmountable when no spare receptors remain." Source 23 also references this in the diagram on the same page, therefore a citation is not needed. --> The former meaning has been standardised by the [[IUPHAR]],<ref name="IUPHAR: Pharmacology terms and symbols" /> and is equivalent to the antagonist being called an ''allosteric antagonist''.<ref name="IUPHAR: Pharmacology terms and symbols" />  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 (physiology)|depression]] of the maximal response of agonist dose-response curves, and in some cases, rightward shifts, is produced.<ref name="Vauquelin2002"/> The rightward shift will occur as a result of a receptor reserve (also known as spare receptors)<ref name=stephanson/> 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.<ref name=Golan25 /> 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.<ref name=Golan25 /> 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.<ref>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}}</ref>  [[Cyclothiazide]] has been shown to act as a reversible non-competitive antagonist of [[Metabotropic glutamate receptor 1|mGluR1 receptor]].<ref name="pmid17095021">{{cite journal | vauthors = Surin A, Pshenichkin S, Grajkowska E, Surina E, Wroblewski JT | title = Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists | journal = Neuropharmacology | volume = 52 | issue = 3 | pages = 744–54 | date = March 2007 | pmid = 17095021 | pmc = 1876747 | doi = 10.1016/j.neuropharm.2006.09.018 }}</ref> Another example of a non-competitive is [[phenoxybenzamine]] which binds irreversibly (with [[covalent bond]]s) to alpha-[[adrenergic receptor]]s, which in turn reduces the fraction of available receptors and reduces the maximal effect that can be produced by the [[agonist]].<ref name=":0">{{Cite web |title=basic_principles_of_pharm [TUSOM {{!}} Pharmwiki] |url=https://tmedweb.tulane.edu/pharmwiki/doku.php/basic_principles_of_pharm |access-date=2023-07-21 |website=tmedweb.tulane.edu |language=en}}</ref>  
[[File:Noncompetitive_a-adrenergic_agonistic_action_of_Phenoxybenzamine.png|thumb|Figure demonstrates the noncompetitive antagonistic behaviour of [[Phenoxybenzamine]] on alpha-adrenergiv norepinephrine receptors.<ref name=":0" />]]

===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".<ref>{{cite journal | vauthors = Lipton SA | title = 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 | journal = NeuroRx | volume = 1 | issue = 1 | pages = 101–10 | date = January 2004 | pmid = 15717010 | pmc = 534915 | doi = 10.1602/neurorx.1.1.101 }}</ref> [[Memantine]], used in the treatment of [[Alzheimer's disease]], is an uncompetitive antagonist of the [[NMDA receptor]].<ref>{{cite journal | vauthors = Parsons CG, Stöffler A, Danysz W | title = 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 | journal = Neuropharmacology | volume = 53 | issue = 6 | pages = 699–723 | date = November 2007 | pmid = 17904591 | doi = 10.1016/j.neuropharm.2007.07.013 | s2cid = 6599658 }}</ref>

===Silent antagonists===
[[File:Ligand response comparison.svg|thumb|Chart demonstrating the difference between agonists, silent antagonists, and inverse agonists<ref name="Rang2020" />]]
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.<ref>{{cite journal | vauthors = Fletcher A, Cliffe IA, Dourish CT | title = Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents | journal = Trends in Pharmacological Sciences| volume = 14 | issue = 12 | pages = 41–48 | date = December 1993 | pmid = 8122313| doi = 10.1016/0165-6147(93)90185-m | s2cid = 4274320 }}</ref>

===Partial agonists===
{{Main|Partial agonist}}

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 [[agonist|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.<ref>Principles and Practice of Pharmacology for Anaesthetists By Norton Elwy Williams, Thomas Norman Calvey Published 2001 Blackwell Publishing {{ISBN|0-632-05605-3}}</ref><ref>{{cite journal | vauthors =Patil PN |title=Everhardus J. Ariëns (1918–2002): a tribute|journal= Trends in Pharmacological Sciences|volume=23 |issue=7 |pages=344–5 |year=2002|doi=10.1016/S0165-6147(02)02068-0}}</ref> 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.<ref>{{cite journal | vauthors = Bosier B, Hermans E | title = Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance | journal =  Trends in Pharmacological Sciences| volume = 28 | issue = 8 | pages = 438–46 | date = August 2007 | pmid = 17629964 | doi = 10.1016/j.tips.2007.06.001 }}</ref><ref>{{cite journal | vauthors = Pulvirenti L, Koob GF | title = Being partial to psychostimulant addiction therapy | journal =  Trends in Pharmacological Sciences| volume = 23 | issue = 4 | pages = 151–3 | date = April 2002 | pmid = 11931978 | doi = 10.1016/S0165-6147(00)01991-X }}</ref> E.g. [[Buprenorphine]], a partial agonist of the [[opioid receptors|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.<ref>{{cite journal | vauthors = Vadivelu N, Hines RL | title = Buprenorphine: a unique opioid with broad clinical applications | journal = Journal of Opioid Management | volume = 3 | issue = 1 | pages = 49–58 | year = 2007 | pmid = 17367094 | doi =  10.5055/jom.2007.0038| doi-access = free }}</ref>

===Inverse agonists===
An [[inverse agonist]] can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses.<ref>{{Cite journal |date=2020-08-19 |title=A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes |journal=Cells |volume=9 |issue=9 |pages=1923 |doi=10.3390/cells9091923 |doi-access=free |issn=2073-4409 |pmc=7564766 |pmid=32825009 |last1=Michel |first1=Martin C. |last2=Michel-Reher |first2=Martina B. |last3=Hein |first3=Peter }}</ref> [[Receptor (biochemistry)#Binding and activation|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;<ref>{{cite journal | vauthors = Greasley PJ, Clapham JC | title = Inverse agonism or neutral antagonism at G-protein coupled receptors: a medicinal chemistry challenge worth pursuing? | journal = European Journal of Pharmacology | volume = 553 | issue = 1–3 | pages = 1–9 | date = December 2006 | pmid = 17081515 | doi = 10.1016/j.ejphar.2006.09.032 }}</ref><ref>{{cite journal | vauthors = Kenakin T | title = Efficacy as a vector: the relative prevalence and paucity of inverse agonism | journal = Molecular Pharmacology | volume = 65 | issue = 1 | pages = 2–11 | date = January 2004 | pmid = 14722230 | doi = 10.1124/mol.65.1.2 | s2cid = 115140 }}</ref>⁠ [[antihistamine]]s for example, originally classified as antagonists of [[histamine]] [[histamine H1 receptor|H<sub>1</sub> receptor]]s, have been reclassified as inverse agonists.<ref>{{cite journal | vauthors = Leurs R, Church MK, Taglialatela M | title = H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects | journal = Clinical and Experimental Allergy | volume = 32 | issue = 4 | pages = 489–98 | date = April 2002 | pmid = 11972592 | doi = 10.1046/j.0954-7894.2002.01314.x | s2cid = 11849647 }}</ref>

==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 [[covalent bond|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, {{em|i.e.}} the rate of synthesis of new receptors. [[Phenoxybenzamine]] is an example of an irreversible [[alpha blocker]]—it permanently binds to [[adrenergic receptor#α receptors|α]] [[adrenergic receptor]]s, preventing [[adrenaline]] and [[noradrenaline]] from binding.<ref>{{cite journal | vauthors = Frang H, Cockcroft V, Karskela T, Scheinin M, Marjamäki A | title = Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors | journal = The Journal of Biological Chemistry | volume = 276 | issue = 33 | pages = 31279–84 | date = August 2001 | pmid = 11395517 | doi = 10.1074/jbc.M104167200 | doi-access = free }}</ref> 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.<ref name="Vauquelin2002"/>

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.<ref name="Lees2004"/> 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.<ref name="Lees2004"/>

== See also ==
* [[Enzyme inhibitor]]
* [[Growth factor receptor inhibitor]]
* [[Selective receptor modulator]]

==References==
{{reflist}}

==External links==
*{{Commons category-inline|Receptor antagonists}}

{{Pharmacology}}
{{Receptor agonists and antagonists}}
{{Authority control}}
{{good article}}

{{DEFAULTSORT:Receptor Antagonist}}
[[Category:Receptor antagonists| ]]
[[Category:Signal transduction]]
[[Category:Pharmacodynamics]]