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{{About|the biochemistry term|other uses|Antagonist (disambiguation)}}
[[Image:Antagonist.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 does not provoke a biological response itself upon binding to a [[Receptor (biochemistry)|receptor]], but blocks or dampens [[agonist]]-mediated responses.<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]." ''[[GlaxoSmithKline|GlaxoWellcome]].'' Retrieved on December 6, 2007.</ref> In [[pharmacology]], '''antagonists''' have [[Dissociation constant#Protein-ligand binding|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 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.<ref name="pmid12209152">{{cite journal |author=Hopkins AL, Groom CR |title=The druggable genome |journal=Nature reviews. Drug discovery |volume=1 |issue=9 |pages=727–30 |year=2002 |pmid=12209152 |doi=10.1038/nrd892}}</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 [[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, occurring on the cell membrane of cells, or [[Intracellular receptor|intracellular]], such as on the [[Cell nucleus|nucleus]] or [[mitochondrion]]. Binding occurs as a result of [[noncovalent]] interaction 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 binding sites.<ref>{{cite journal |author=May LT, Avlani VA, Sexton PM, Christopoulos A |title=Allosteric modulation of G protein-coupled receptors |journal=Curr. Pharm. Des. |volume=10 |issue=17 |pages=2003–13 |year=2004 |pmid=15279541|doi=10.2174/1381612043384303}}</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 |author=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 |year=2002 |pmid=12120504|doi=10.1038/nrd746}}</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 |author=Bleicher KH, Green LG, Martin RE, Rogers-Evans M |title=Ligand identification for G-protein-coupled receptors: a lead generation perspective |journal=Curr Opin Chem Biol |volume=8 |issue=3 |pages=287–96 |year=2004 |pmid=15183327 |doi=10.1016/j.cbpa.2004.04.008}}</ref><ref>{{cite journal |author=Rees S, Morrow D, Kenakin T |title=GPCR drug discovery through the exploitation of allosteric drug binding sites |journal=Recept. 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 |author=Negus SS |title=Some implications of receptor theory for in vivo assessment of agonists, antagonists and inverse agonists |journal=Biochem. Pharmacol. |volume=71 |issue=12 |pages=1663–70 |year=2006 |pmid=16460689 |doi=10.1016/j.bcp.2005.12.038 |pmc=1866283}}</ref> The biochemical definition of a receptor antagonist was introduced by Ariens<ref>{{cite journal |author=Ariëns 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 |year=1954 |pmid=13229418 |doi=}}</ref> and Stephenson<ref name=stephanson>{{cite journal |author=Stephenson RP |title=A modification of receptor theory. 1956 |journal=Br. J. Pharmacol. |volume=120 |issue=4 Suppl |pages=106–20; discussion 103–5 |year=1997 |pmid=9142399 |doi=}} {{PMC|1510558}} 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 [[β-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 |author=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 |year=2005 |pmid=15660959 |doi=10.1111/j.1472-8206.2005.00319.x}}</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 |author=Urban JD, Clarke WP, von Zastrow M, ''et al.'' |title=Functional selectivity and classical concepts of quantitative pharmacology |journal=J. Pharmacol. Exp. Ther. |volume=320 |issue=1 |pages=1–13 |year=2007 |pmid=16803859 |doi=10.1124/jpet.106.104463}}</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===
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]] of an antagonist is usually defined by its [[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 |author=Lees P, Cunningham FM, Elliott J |title=Principles of pharmacodynamics and their applications in veterinary pharmacology |journal=J. Vet. Pharmacol. Ther. |volume=27 |issue=6 |pages=397–414 |year=2004 |pmid=15601436 |doi=10.1111/j.1365-2885.2004.00620.x}}</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 |author=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 |year=2004 |pmid=15340390 |doi=10.1038/nrd1500}}</ref>

===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 [[IC50|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 |author=Wyllie DJ, Chen PE |title=Taking the time to study competitive antagonism |journal=Br. J. Pharmacol. |volume=150 |issue=5 |pages=541–51 |year=2007 |pmid=17245371 |doi=10.1038/sj.bjp.0706997 |pmc=2189774}}</ref><ref>{{cite journal |author=Colquhoun D |title=Why the Schild method is better than Schild realised |journal=Trends Pharmacol Sci |volume= 28|issue=  12|pages=608|year=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 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 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 |author=Schild HO |title=An ambiguity in receptor theory |journal=Br. J. Pharmacol. |volume=53 |issue=2 |pages=311 |year=1975 |pmid=1148491 |doi= |pmc=1666289}}</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 |author=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=Biochem. Pharmacol. |volume=22 |issue=23 |pages=3099–108 |year=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==
===Competitive===
[[Competitive antagonist]]s (also known as surmountable antagonists) reversibly 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. 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 shifts of agonist dose–response curves with no alteration of the maximal response is observed.<ref name="Vauquelin2002">{{cite journal |author=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 |year=2002 |pmid=12570014 |doi=10.1046/j.1472-8206.2002.00095.x}}</ref> The [[interleukin-1]] receptor antagonist, [[IL1ra|IL-1Ra]] is an example of a competitive antagonist.<ref name="pmid8379462">{{cite journal |author=Arend WP |title=Interleukin-1 receptor antagonist |journal=Adv. Immunol. |volume=54 |issue= |pages=167–227 |year=1993 |pmid=8379462 |doi=10.1016/S0065-2776(08)60535-0}}</ref> 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 (sometimes called non-surmountable antagonists) are [[allosteric]] 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 [[Metabotropic glutamate receptor 1|mGluR1 receptor]].<ref  name="pmid17095021">{{cite journal |author=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 |year=2007 |pmid=17095021 |doi=10.1016/j.neuropharm.2006.09.018 |pmc=1876747}}</ref> Non-competitive antagonists do not compete with agonists for binding. 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> 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.<ref name="Vauquelin2002"/> The rightward shift will occur as a result of a receptor reserve<ref name=stephanson/> 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".<ref>{{cite journal |author=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 : the journal of the American Society for Experimental NeuroTherapeutics |volume=1 |issue=1 |pages=101–10 |year=2004 |pmid=15717010 |doi= |pmc=534915}}</ref> [[Memantine]], used in the treatment of [[Alzheimer's disease]], is an uncompetitive antagonist of the [[NMDA receptor]].<ref>{{cite journal |author=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 |year=2007 |pmid=17904591 |doi=10.1016/j.neuropharm.2007.07.013}}</ref>

===Silent antagonists===

Silent antagonists are competitive receptor antagonists that have zero [[Efficacy|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 agonist]]s or [[inverse agonist]]s.

===Partial agonists===

[[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 |author=Patil PN |title=Everhardus J. Ariëns (1918–2002): a tribute|journal=Trends Pharmacol. Sci. |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 |author=Bosier B, Hermans E |title=Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance |journal=Trends Pharmacol. Sci. |volume=28 |issue=8 |pages=438–46 |year=2007 |pmid=17629964 |doi=10.1016/j.tips.2007.06.001}}</ref><ref>{{cite journal |author=Pulvirenti L, Koob GF |title=Being partial to psychostimulant addiction therapy |journal=Trends Pharmacol. Sci. |volume=23 |issue=4 |pages=151–3 |year=2002 |pmid=11931978|doi=10.1016/S0165-6147(00)01991-X}}</ref> [[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 in reversing morphine addiction as an alternative to [[methodone]] in the treatment of drug addiction.<ref>{{cite journal |author=Vadivelu N, Hines RL |title=Buprenorphine: a unique opioid with broad clinical applications |journal=J Opioid Manag |volume=3 |issue=1 |pages=49–58 |year=2007 |pmid=17367094 |doi=}}</ref>

===Inverse agonists===
An [[inverse agonist]] can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses. [[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 |author=Greasley PJ, Clapham JC |title=Inverse agonism or neutral antagonism at G-protein coupled receptors: a medicinal chemistry challenge worth pursuing? |journal=Eur. J. Pharmacol. |volume=553 |issue=1-3 |pages=1–9 |year=2006 |pmid=17081515 |doi=10.1016/j.ejphar.2006.09.032}}</ref><ref>{{cite journal |author=Kenakin T |title=Efficacy as a vector: the relative prevalence and paucity of inverse agonism |journal=Mol. Pharmacol. |volume=65 |issue=1 |pages=2–11 |year=2004 |pmid=14722230 |doi=10.1124/mol.65.1.2}}</ref> [[Antihistamine]]s, originally classified as antagonists of [[histamine]] [[histamine H1 receptor|H<sub>1</sub> receptor]]s have been reclassified as inverse agonists.<ref>{{cite journal | author=Leurs R, Church MK, Taglialatela M | year=2002 | title=H<sub>1</sub>-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects | journal=Clin Exp Allergy | volume=32 | issue=4 | pages=489–98 | pmid=11972592 | doi=10.1046/j.0954-7894.2002.01314.x}}</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, the rate of synthesis of new receptors. [[Phenoxybenzamine]] is an example of an irreversible [[alpha blocker]]&mdash;it permanently binds to [[adrenergic receptor#α receptors|α]] [[adrenergic receptor]]s, preventing [[adrenaline]] and [[noradrenaline]] from binding.<ref>{{cite journal |author=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=J. Biol. Chem. |volume=276 |issue=33 |pages=31279–84 |year=2001 |pmid=11395517 |doi=10.1074/jbc.M104167200}}</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 antagonist, there may be a distinct period during which they behave competitively (regardless of basal efficiacy), 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==
{{Portal|Pharmacy and Pharmacology}}

* [[Receptor theory]]
* [[Agonist]]
* [[Enzyme inhibitor]]
* [[efficacy#Pharmacology|Efficacy]]
* [[dissociation constant#Protein-ligand binding|Affinity]]
* [[Barbourin]]
* [[Inverse agonist]]
* [[Mixed agonist/antagonist]]

==References==
{{Reflist|2}}

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

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

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