Editing Inverse agonist

{{Short description|Agent in biochemistry}}
{{distinguish|Antagonist (disambiguation){{!}}Antagonist|Protagonist (disambiguation){{!}}Protagonist}}
[[Image:Inverse agonist 3.svg|thumb|400 px|Dose response curves of a full agonist, partial agonist, neutral antagonist, and inverse agonist]]
In [[pharmacology]], an '''inverse agonist''' is a [[drug]] that binds to the same [[receptor (biochemistry)|receptor]] as an [[agonist]] but induces a pharmacological response opposite to that of the agonist.

A [[receptor antagonist|neutral antagonist]] has no activity in the absence of an agonist or inverse agonist but can block the activity of either;<ref>{{cite journal | vauthors = Kenakin T | title = Principles: receptor theory in pharmacology | journal = Trends in Pharmacological Sciences | volume = 25 | issue = 4 | pages = 186–92 | date = April 2004 | pmid = 15063082 | doi = 10.1016/j.tips.2004.02.012 }}</ref> they are in fact sometimes called ''blockers'' (examples include [[alpha blocker]]s, [[beta blocker]]s, and [[calcium channel blocker]]s). Inverse agonists have opposite actions to those of agonists but the effects of both of these can be blocked by antagonists.<ref name="pmid27955830">{{cite journal | vauthors = Nutt D, Stahl S, Blier P, Drago F, Zohar J, Wilson S |author-link1=David Nutt |title = Inverse agonists - What do they mean for psychiatry? | journal = European Neuropsychopharmacology | volume = 27 | issue = 1 | pages = 87–90 | date = January 2017 | pmid = 27955830 | doi = 10.1016/j.euroneuro.2016.11.013 | hdl = 10044/1/43624 |s2cid=25113284 | hdl-access = free }}</ref>

A prerequisite for an inverse agonist response is that the receptor must have a [[receptor (biochemistry)#Constitutive activity|constitutive]] (also known as [[intrinsic activity|intrinsic]] or basal) level of activity in the absence of any [[ligand (biochemistry)|ligand]].<ref>{{Cite journal|last1=Berg|first1=Kelly A|last2=Clarke|first2=William P|date=2018-08-06|title=Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity|journal=International Journal of Neuropsychopharmacology|volume=21|issue=10|pages=962–977|doi=10.1093/ijnp/pyy071|issn=1461-1457|pmc=6165953|pmid=30085126}}</ref> An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level.

The [[efficacy]] of a full agonist is by definition 100%, a neutral antagonist has 0% efficacy, and an inverse agonist has < 0% (i.e., negative) efficacy.

==Examples==
Receptors for which inverse agonists have been identified include the [[GABAA|GABA<sub>A</sub>]], [[melanocortin receptor|melanocortin]], [[mu opioid receptor|mu opioid]], [[histamine receptor|histamine]] and [[beta adrenergic receptor]]s. Both [[Endogeny (biology)|endogenous]] and [[Exogeny|exogenous]] inverse agonists have been identified, as have drugs at ligand gated ion channels and at G protein-coupled receptors.

=== Ligand gated ion channel inverse agonists ===
An example of a receptor site that possesses basal activity and for which inverse agonists have been identified is the [[GABAA receptors|GABA<sub>A</sub> receptors]]. Agonists for GABA<sub>A</sub> receptors (such as [[muscimol]]) create a [[relaxant]] effect, whereas inverse agonists have [[agitation (action)|agitation]] effects (for example, [[Ro15-4513]]) or even [[convulsive]] and [[anxiogenic]] effects (certain [[beta-carboline]]s).<ref>{{cite journal|vauthors=Mehta AK, Ticku MK|date=August 1988|title=Ethanol potentiation of GABAergic transmission in cultured spinal cord neurons involves gamma-aminobutyric acid voltage-gated chloride channels|url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2457076|journal=The Journal of Pharmacology and Experimental Therapeutics|volume=246|issue=2|pages=558–64|pmid=2457076|access-date=2008-04-21|archive-date=2021-05-31|archive-url=https://web.archive.org/web/20210531145604/https://jpet.aspetjournals.org/content/246/2/558.long|url-status=live}}</ref><ref>{{cite journal|vauthors=Sieghart W|date=January 1994|title=Pharmacology of benzodiazepine receptors: an update|journal=Journal of Psychiatry & Neuroscience|volume=19|issue=1|pages=24–9|pmc=1188559|pmid=8148363}}</ref>

=== G protein-coupled receptor inverse agonists ===
<!--Endogenous examples-->
Two known endogenous inverse agonists are the [[Agouti-related peptide]] (AgRP) and its associated peptide [[Agouti signalling peptide]] (ASIP). AgRP and ASIP appear naturally in humans and bind [[melanocortin receptors]] 4 and 1 ([[melanocortin 4 receptor|Mc4R]] and [[melanocortin 1 receptor|Mc1R]]), respectively, with nanomolar affinities.<ref name="pmid9450927">{{cite journal|vauthors=Ollmann MM, Lamoreux ML, Wilson BD, Barsh GS|date=February 1998|title=Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo|journal=Genes & Development|volume=12|issue=3|pages=316–30|doi=10.1101/gad.12.3.316|pmc=316484|pmid=9450927}}</ref>

<!--Exogenous examples-->
The [[opioid antagonist]]s [[naloxone]] and [[naltrexone]] act as [[Receptor antagonist|neutral antagonists]] of the [[mu opioid receptors]] under basal conditions, but as inverse agonists when an opioid such as [[morphine]] is bound to the same channel. 6α-naltrexo, [[6β-Naltrexol|6β-naltrexol]], 6β-naloxol, and 6β-naltrexamine acted [[Receptor antagonist|neutral antagonists]] regardless of opioid binding and caused significantly reduced withdrawal jumping when compared to [[naloxone]] and [[naltrexone]].<ref name="pmid11413242">{{cite journal|vauthors=Wang OD, Raehal KM, Bilsky EJ, Sadée W|date=June 2001|title=Inverse agonists and neutral antagonists at mu opioid receptor (MOR): possible role of basal receptor signaling in narcotic dependence |journal= Journal of Neurochemistry|volume=77|issue=3|pages=1590–600|doi=10.1046/j.1471-4159.2001.00362.x|pmid=11413242|s2cid=10026688 |doi-access=free}}</ref>

Nearly all antihistamines acting at [[H1 receptors]] and [[H2 receptors]] have been shown to be inverse agonists.<ref name=":0">{{cite journal| pmc=3195115 | pmid=22021988 | doi=10.4103/0253-7613.84947 | volume=43 | issue=5 | title=Inverse agonism and its therapeutic significance | year=2011 | journal=Indian J Pharmacol | pages=492–501 | author=Khilnani G, Khilnani AK | doi-access=free }}</ref>

The [[beta blockers]] [[carvedilol]] and [[bucindolol]] have been shown to be low level inverse agonists at [[beta adrenoceptors]].<ref name=":0" />

== Mechanisms of action ==
[[File:Basal_activity_of_receptor_changes.png|thumb|431x431px|Figure 2: Example of changes in Intrinsic activity based on mutations and the presence of inverse agonists. (assuming the inverse agonist has the same binding affinity for both the normal and mutated receptor)]]
Like [[Agonist|agonists]], inverse agonists have their own unique ways of inducing pharmacological and physiological responses depending on many factors, such as the type of inverse agonist, the type of [[Receptor (biochemistry)|receptor]], mutants of receptors, binding affinities and whether the effects are exerted acutely or chronically based on receptor population density.<ref name=":2">{{Cite journal |last=Prather |first=Paul L. |date=2004-01-05 |title=Inverse agonists: tools to reveal ligand-specific conformations of G protein-coupled receptors |url=https://pubmed.ncbi.nlm.nih.gov/14722344/ |journal=Science's STKE: Signal Transduction Knowledge Environment |volume=2004 |issue=215 |pages=pe1 |doi=10.1126/stke.2152004pe1 |issn=1525-8882 |pmid=14722344|s2cid=22336235 }}</ref> Because of this, they exhibit a spectrum of activity below the [[Intrinsic activity]] level.<ref name=":2" /><ref name=":1">{{Cite journal |last1=Hirayama |first1=Shigeto |last2=Fujii |first2=Hideaki |date=2020 |title=δ Opioid Receptor Inverse Agonists and their In Vivo Pharmacological Effects |url=https://pubmed.ncbi.nlm.nih.gov/32238139/ |journal=Current Topics in Medicinal Chemistry |volume=20 |issue=31 |pages=2889–2902 |doi=10.2174/1568026620666200402115654 |issn=1873-4294 |pmid=32238139|s2cid=214767114 }}</ref> Changes in constitutive activity of receptors affect response levels from ligands like inverse agonists.<ref>{{Cite journal |last1=Berg |first1=Kelly A. |last2=Clarke |first2=William P. |date=2018-10-01 |title=Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity |journal=The International Journal of Neuropsychopharmacology |volume=21 |issue=10 |pages=962–977 |doi=10.1093/ijnp/pyy071 |issn=1469-5111 |pmc=6165953 |pmid=30085126}}</ref>

To illustrate, mechanistic models have been made for how inverse agonists induce their responses on [[G protein-coupled receptor]]s (GPCRs). Many types of Inverse agonists for [[G protein-coupled receptor|GPCRs]] have been shown to exhibit the following conventionally accepted mechanism.

Based on the Extended [[Ternary complex]] model, the mechanism contends that inverse agonists switch the receptor from an active state to an inactive state by undergoing conformational changes.<ref name=":02">{{Cite journal |last=Strange |first=Philip G. |date=February 2002 |title=Mechanisms of inverse agonism at G-protein-coupled receptors |url=https://pubmed.ncbi.nlm.nih.gov/11830266/ |journal=Trends in Pharmacological Sciences |volume=23 |issue=2 |pages=89–95 |doi=10.1016/s0165-6147(02)01993-4 |issn=0165-6147 |pmid=11830266}}</ref> Under this model, current thinking is that the [[G protein-coupled receptor|GPCRs]] can exist in a continuum of active and inactive states when no ligand is present.<ref name=":02" /> Inverse agonists stabilize the inactive states, thereby suppressing agonist-independent activity.<ref name=":02" /> However, the implementation of 'constitutively active mutants'<ref name=":02" /> of [[G protein-coupled receptor|GPCRs]] change their intrinsic activity.<ref name=":2" /><ref name=":1" /> Thus, the effect an inverse agonist has on a receptor depends on the basal activity of the receptor, assuming the inverse agonist has the same binding affinity (as shown in the figure 2).

== See also ==
*[[Agonist]]
*[[Receptor antagonist]]
*[[Autoreceptor]]

== References ==
{{reflist}}

== External links ==
* {{cite web |url= https://medicine.creighton.edu/courses/pharm/Dr.Jeffries/Inverse.asp |title= Inverse Agonists for Medical Students |author= Jeffries WB |date= 1999-02-17 |work= Office of Medical Education - Courses - IDC 105 Principles of Pharmacology |publisher= Creighton University School of Medicine - Department of Pharmacology |access-date= 2008-08-12 }}{{Dead link|date=March 2022 |bot=InternetArchiveBot |fix-attempted=yes }}
*[http://pharmacologycorner.com/inverse-agonists/ Inverse Agonists: An Illustrated Tutorial] Panesar K, Guzman F. Pharmacology Corner. 2012
{{Pharmacology}}

[[Category:Pharmacodynamics]]
[[Category:Receptor agonists]]