View source for 5-HT2A receptor

{{DISPLAYTITLE:5-HT<sub>2A</sub> receptor}}
{{Infobox_gene}}
The mammalian '''5-HT<sub>2A</sub> receptor''' is a subtype of the [[5-HT2 receptor|5-HT<sub>2</sub> receptor]] that belongs to the [[serotonin receptor]] family and is a [[GPCR|G protein-coupled receptor]] (GPCR).<ref name="pmid8035173">{{cite journal | vauthors = Cook EH, Fletcher KE, Wainwright M, Marks N, Yan SY, Leventhal BL | title = Primary structure of the human platelet serotonin 5-HT<sub>2A</sub> receptor: identify with frontal cortex serotonin 5-HT<sub>2A</sub> receptor | journal = Journal of Neurochemistry | volume = 63 | issue = 2 | pages = 465–9 | date = August 1994 | pmid = 8035173 | doi = 10.1046/j.1471-4159.1994.63020465.x }}</ref> 5-HT is short for 5-hydroxy-tryptamine, which is serotonin. This is the main excitatory receptor subtype among the [[GPCR]]s for [[serotonin]], although 5-HT<sub>2A</sub> may also have an inhibitory effect<ref>{{cite journal | vauthors = Martin P, Waters N, Schmidt CJ, Carlsson A, Carlsson ML | title = Rodent data and general hypothesis: antipsychotic action exerted through 5-HT<sub>2A</sub> receptor antagonism is dependent on increased serotonergic tone | journal = Journal of Neural Transmission | volume = 105 | issue = 4-5 | pages = 365–96 | year = 1998 | pmid = 9720968 | doi = 10.1007/s007020050064 }}</ref> on certain areas such as the [[visual cortex]] and the orbitofrontal cortex.<ref name="De AlmeidaRosa2006">{{cite journal | vauthors = De Almeida RM, Rosa MM, Santos DM, Saft DM, Benini Q, Miczek KA | title = 5-HT(1B) receptors, ventral orbitofrontal cortex, and aggressive behavior in mice | journal = Psychopharmacology | volume = 185 | issue = 4 | pages = 441–50 | date = May 2006 | pmid = 16550387 | doi = 10.1007/s00213-006-0333-3 }}</ref>  This receptor was first noted for its importance as a target of [[Psychedelic drug#Serotonergic psychedelics (5-HT2A receptor agonists)|serotonergic psychedelic drugs]] such as [[LSD]]. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many [[antipsychotic]] drugs, especially the [[atypical antipsychotic|atypical]] ones.

5-HT<sub>2A</sub> may be a necessary receptor for the spread of the human [[polyoma virus]] called the [[JC virus]].<ref name="pmid15550673">{{cite journal | vauthors = Elphick GF, Querbes W, Jordan JA, Gee GV, Eash S, Manley K, Dugan A, Stanifer M, Bhatnagar A, Kroeze WK, Roth BL, Atwood WJ | title = The human polyomavirus, JCV, uses serotonin receptors to infect cells | journal = Science | volume = 306 | issue = 5700 | pages = 1380–3 | date = November 2004 | pmid = 15550673 | doi = 10.1126/science.1103492 }}</ref>

Downregulation of post-synaptic 5-HT<sub>2A</sub> receptor is an adaptive process provoked by chronic administration of [[selective serotonin reuptake inhibitor]]s (SSRIs) and classical antipsychotics. Suicidal and otherwise depressed patients have had more 5-HT<sub>2A</sub> receptors than normal patients. These findings suggest that post-synaptic 5-HT<sub>2A</sub> overdensity is involved in the pathogenesis of depression.<ref name=pmid8788498>{{cite journal | vauthors = Eison AS, Mullins UL | title = Regulation of central 5-HT<sub>2A</sub> receptors: a review of in vivo studies | journal = Behavioural Brain Research | volume = 73 | issue = 1–2 | pages = 177–81 | year = 1996 | pmid = 8788498 | doi = 10.1016/0166-4328(96)00092-7 }}</ref>

Paradoxical down-regulation of 5-HT<sub>2A</sub> receptors can be observed with several 5-HT<sub>2A</sub> antagonists.<ref name=":2">{{cite journal | vauthors = Yadav PN, Kroeze WK, Farrell MS, Roth BL | title = Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 339 | issue = 1 | pages = 99–105 | date = October 2011 | pmid = 21737536 | pmc = 3186284 | doi = 10.1124/jpet.111.183780 }}</ref> Thus, instead of tolerance, [[Reverse tolerance|reverse-tolerance]] would be expected from 5-HT<sub>2A</sub> antagonists. However, there is at least one antagonist at this site which has been shown to up-regulate 5-HT<sub>2A</sub> receptors.<ref name=":2" /><ref>{{cite journal | vauthors = Rinaldi-Carmona M, Congy C, Simiand J, Oury-Donat F, Soubrie P, Breliere JC, Le Fur G | title = Repeated administration of SR 46349B, a selective 5-hydroxytryptamine2 antagonist, up-regulates 5-hydroxytryptamine2 receptors in mouse brain | journal = Molecular Pharmacology | volume = 43 | issue = 1 | pages = 84–9 | date = January 1993 | pmid = 8423772 }}</ref> Additionally, a couple of other antagonists may have no effect on 5-HT<sub>2A</sub> receptor number.<ref>{{cite journal | vauthors = Gray JA, Roth BL | title = Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists | journal = Brain Research Bulletin | volume = 56 | issue = 5 | pages = 441–51 | date = November 2001 | pmid = 11750789 }}</ref> Nevertheless, upregulation is the exception rather than the rule. Neither [[Drug tolerance|tolerance]] nor [[Rebound effect|rebound]] is observed in humans with regard to the [[Slow-wave sleep|SWS]] promoting effects of 5-HT<sub>2A</sub> antagonists.<ref>{{cite journal | vauthors = Vanover KE, Davis RE | title = Role of 5-HT2A receptor antagonists in the treatment of insomnia | journal = Nature and Science of Sleep | volume = 2 | pages = 139–50 | date = 2010-07-28 | pmid = 23616706 | pmc = 3630942 }}</ref>

== History ==
Serotonin receptors were split into two classes by Gaddum and Picarelli when it was discovered that some of the serotonin-induced changes in the [[Gut (zoology)|gut]] could be blocked by [[morphine]], whilst the remainder of the response was inhibited by [[Phenoxybenzamine|dibenzyline]] leading to the naming of M and D receptors respectively.  5-HT<sub>2A</sub> is thought to correspond to what was originally described as D subtype of [[5-HT receptor]]s by Gaddum and Picarelli.<ref name="isbn0-07-142280-3">{{cite book| vauthors = Sanders-Bush E, Mayer SE| editor = Brunton LL |editor2=Lazo JS |editor3=Parker K| others =| title = Goodman & Gilman's the Pharmacological Basis of Therapeutics| edition = 11th| publisher = McGraw-Hill| location = New York| year = 2006| pages =| chapter = Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists| isbn = 0-07-142280-3| oclc =| doi =| url = }}</ref> In the pre-molecular-cloning era when [[radioligand]] binding and displacement was the only major tool, spiperone and LSD were shown to label two different serotonin receptors, and neither of them displaced morphine, leading to naming of the [[5-HT1 receptor|5-HT<sub>1</sub>]], [[5-HT2 receptor|5-HT<sub>2</sub>]] and [[5-HT3 receptor|5-HT<sub>3</sub>]] receptors, corresponding to high affinity sites from [[LSD]], [[spiperone]] and morphine respectively.<ref>{{cite book |title=Basic neurochemistry: molecular, cellular, and medical aspects |volume=1 | first1 = George J. | last1 = Siegel | first2 = R. Wayne | last2 = Albers | name-list-format = vanc |edition=7th |isbn=0-12-088397-X |publisher=Academic Press |year=2005 |url=https://books.google.com/books?id=Af0IyHtGCMUC&pg=PA241 |pages=241}}</ref> Later it was shown that the 5-HT<sub>2</sub> was very close to 5-HT<sub>1C</sub> and thus were clubbed together, renaming the 5-HT<sub>2</sub> into 5-HT<sub>2A</sub>. Thus the 5-HT<sub>2</sub> receptor family is composed of three separate molecular entities: the 5-HT<sub>2A</sub> (formerly known as 5-HT<sub>2</sub> or D), the [[5-HT2B|5-HT<sub>2B</sub>]] (formerly known as 5-HT<sub>2F</sub>) and the [[5-HT2C|5-HT<sub>2C</sub>]] (formerly known as 5-HT<sub>1C</sub>) receptors.<ref name="Hoyer_2002">{{cite journal | vauthors = Hoyer D, Hannon JP, Martin GR | title = Molecular, pharmacological and functional diversity of 5-HT receptors | journal = Pharmacology Biochemistry and Behavior | volume = 71 | issue = 4 | pages = 533–54 | date = April 2002 | pmid = 11888546 | doi = 10.1016/S0091-3057(01)00746-8 }}</ref>

== Distribution ==
5-HT<sub>2A</sub> is expressed widely throughout the [[central nervous system]] (CNS).
It is expressed near most of the serotoninergic terminal rich areas, including [[neocortex]] (mainly [[prefrontal cortex|prefrontal]], [[parietal cortex|parietal]], and [[somatosensory cortex]]) and the [[olfactory tubercle]]. Especially high concentrations of this receptor on the [[apical dendrite]]s of [[pyramidal cell]]s in [[layer V]] of the cortex may modulate cognitive processes, working memory, and attention<ref name="pmid10216183">{{cite journal | vauthors = Aghajanian GK, Marek GJ | title = Serotonin, via 5-HT<sub>2A</sub> receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release | journal = Brain Research | volume = 825 | issue = 1–2 | pages = 161–71 | date = April 1999 | pmid = 10216183 | doi = 10.1016/S0006-8993(99)01224-X }}</ref><ref name="pmid11672605">{{cite journal | vauthors = Marek GJ, Wright RA, Gewirtz JC, Schoepp DD | title = A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex | journal = Neuroscience | volume = 105 | issue = 2 | pages = 379–92 | year = 2001 | pmid = 11672605 | doi = 10.1016/S0306-4522(01)00199-3 }}</ref><ref name="pmid16277612">{{cite journal | vauthors = Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F | title = The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity | journal = Journal of Neurochemistry | volume = 95 | issue = 6 | pages = 1597–607 | date = December 2005 | pmid = 16277612 | doi = 10.1111/j.1471-4159.2005.03485.x }}</ref> by enhancing [[glutamate]] release followed by a complex range of interactions with the [[5-HT1A receptor|5-HT<sub>1A</sub>]],<ref name="pmid14754868">{{cite journal | vauthors = Amargós-Bosch M, Bortolozzi A, Puig MV, Serrats J, Adell A, Celada P, Toth M, Mengod G, Artigas F | title = Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex | journal = Cerebral Cortex | volume = 14 | issue = 3 | pages = 281–99 | date = March 2004 | pmid = 14754868 | doi = 10.1093/cercor/bhg128 }}</ref> [[GABAA receptor|GABA<sub>A</sub>]],<ref name="pmid11517239">{{cite journal | vauthors = Feng J, Cai X, Zhao J, Yan Z | title = Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons | journal = The Journal of Neuroscience | volume = 21 | issue = 17 | pages = 6502–11 | date = September 2001 | pmid = 11517239 | doi =  }}</ref> [[Adenosine A1 receptor|adenosine A<sub>1</sub>]],<ref>{{cite journal | vauthors = Marek GJ | title = Activation of adenosine(1) (A(1)) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats | journal = Neuropharmacology | volume = 56 | issue = 8 | pages = 1082–7 | date = June 2009 | pmid = 19324062 | pmc = 2706691 | doi = 10.1016/j.neuropharm.2009.03.005 }}</ref> [[AMPA receptor|AMPA]],<ref>{{cite journal | vauthors = Zhang C, Marek GJ | title = AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 32 | issue = 1 | pages = 62–71 | date = January 2008 | pmid = 17728034 | doi = 10.1016/j.pnpbp.2007.07.009 }}</ref> [[Metabotropic glutamate receptor#Classification|mGluR<sub>2/3</sub>]],<ref>{{cite journal | vauthors = Gewirtz JC, Marek GJ | title = Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors | journal = Neuropsychopharmacology | volume = 23 | issue = 5 | pages = 569–76 | date = November 2000 | pmid = 11027922 | doi = 10.1016/S0893-133X(00)00136-6 }}</ref> [[Metabotropic glutamate receptor 5|mGlu5]],<ref name="pmid18621097">{{cite journal | vauthors = Marek GJ, Zhang C | title = Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex | journal = Neuroscience Letters | volume = 442 | issue = 3 | pages = 239–43 | date = September 2008 | pmid = 18621097 | pmc = 2677702 | doi = 10.1016/j.neulet.2008.06.083 }}</ref> and [[Hypocretin (orexin) receptor 2|OX<sub>2</sub>]] receptors.<ref name="pmid17656637">{{cite journal | vauthors = Lambe EK, Liu RJ, Aghajanian GK | title = Schizophrenia, hypocretin (orexin), and the thalamocortical activating system | journal = Schizophrenia Bulletin | volume = 33 | issue = 6 | pages = 1284–90 | date = November 2007 | pmid = 17656637 | pmc = 2779889 | doi = 10.1093/schbul/sbm088 }}</ref><ref name="pmid18172209">{{cite journal | vauthors = Liu RJ, Aghajanian GK | title = Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 1 | pages = 359–64 | date = January 2008 | pmid = 18172209 | pmc = 2224217 | doi = 10.1073/pnas.0706679105 }}</ref> In the rat cerebellum, the protein has also been found in the [[Golgi cell]]s of the [[granular layer (cerebral cortex)|granular layer]],<ref name="pmid12084412">{{cite journal | vauthors = Geurts FJ, De Schutter E, Timmermans JP | title = Localization of 5-HT<sub>2A</sub>, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum | journal = Journal of Chemical Neuroanatomy | volume = 24 | issue = 1 | pages = 65–74 | date = June 2002 | pmid = 12084412 | doi = 10.1016/S0891-0618(02)00020-0 }}</ref> and in the [[Purkinje cell]]s.<ref name="pmid9756362">{{cite journal | vauthors = Maeshima T, Shutoh F, Hamada S, Senzaki K, Hamaguchi-Hamada K, Ito R, Okado N | title = Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells | journal = Neuroscience Letters | volume = 252 | issue = 1 | pages = 72–4 | date = August 1998 | pmid = 9756362 | doi = 10.1016/S0304-3940(98)00546-1 }}</ref><ref name="pmid15567478">{{cite journal | vauthors = Maeshima T, Shiga T, Ito R, Okado N | title = Expression of serotonin2A receptors in Purkinje cells of the developing rat cerebellum | journal = Neuroscience Research | volume = 50 | issue = 4 | pages = 411–7 | date = December 2004 | pmid = 15567478 | doi = 10.1016/j.neures.2004.08.010 }}</ref>

In the periphery, it is highly expressed in [[platelets]] and many cell types of the [[cardiovascular]] system, in [[fibroblast]]s, and in neurons of the peripheral nervous system. Additionally, 5-HT<sub>2A</sub> mRNA expression has been observed in human [[monocytes]].<ref name="pmid15802305">{{cite journal | vauthors = Dürk T, Panther E, Müller T, Sorichter S, Ferrari D, Pizzirani C, Di Virgilio F, Myrtek D, Norgauer J, Idzko M | title = 5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes | journal = [[International Immunology]] | volume = 17 | issue = 5 | pages = 599–606 | date = May 2005 | pmid = 15802305 | doi = 10.1093/intimm/dxh242 }}</ref>

== Signaling cascade ==
The 5-HT<sub>2A</sub> receptor is known primarily to couple to the Gα<sub>q</sub> signal transduction pathway. Upon receptor stimulation with agonist, Gα<sub>q</sub> and β-γ subunits dissociate to initiate downstream effector pathways.  Gα<sub>q</sub> stimulates [[phospholipase C]] (PLC) activity, which subsequently promotes the release of [[diglyceride|diacylglycerol]]&nbsp;(DAG) and [[inositol triphosphate]]&nbsp;(IP3), which in turn stimulate [[protein kinase C]]&nbsp;(PKC) activity and [[Ca2+|Ca<sup>2+</sup>]] release.<ref name="pmid16803859">{{cite journal | 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 }}</ref>

There are many additional signal cascade components that include the formation of [[arachidonic acid]] through [[PLA2]] activity, activation of [[phospholipase D]], [[Rho family of GTPases|Rho]]/[[Rho kinase]], and [[Extracellular signal-regulated kinases|ERK]] pathway activation initiated by agonist stimulation of the receptor.{{Citation needed|date=November 2007}}

== Effects ==
Physiological processes mediated by the receptor include:
* CNS: neuronal excitation (most likely responsible for the psychedelic effects associated with 5-HT<sub>2A</sub> receptor agonists such as [[LSD]], [[N,N-Dimethyltryptamine|DMT]], etc.),<ref name="ReferenceA">{{cite journal | vauthors = Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J | title = Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT<sub>2A</sub> receptor agonists | journal = Neuroscience Letters | volume = 493 | issue = 3 | pages = 76–9 | date = April 2011 | pmid = 21276828 | pmc = 3064746 | doi = 10.1016/j.neulet.2011.01.046 }}</ref> behavioural effects, learning, anxiety, and pro-nociception<ref>{{Cite journal | vauthors = Patel R, Dickenson AH | date = September 2018 | title = Modality selective roles of pro-nociceptive spinal 5-HT2A and 5-HT3 receptors in normal and neuropathic states |journal=Neuropharmacology |doi=10.1016/j.neuropharm.2018.09.028 }}</ref>
* smooth muscle: contraction (in [[bronchi]] and [[gastrointestinal tract]])
* [[vasoconstriction]] / [[vasodilation]]
* platelets: [[platelet aggregation|aggregation]]
* Activation of the 5-HT<sub>2A</sub> receptor with [[2,5-Dimethoxy-4-iodoamphetamine]] (DOI) produces potent [[anti-inflammatory]] effects in several tissues including cardiovascular and gut. Other 5-HT<sub>2A</sub> agonists like LSD also have potent anti-inflammatory effects against [[TNF-alpha]]-induced [[inflammation]].<ref>{{cite journal | vauthors = Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD | title = Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 2 | pages = 316–23 | date = November 2008 | pmid = 18708586 | doi = 10.1124/jpet.108.143461 }}</ref><ref>{{cite journal | vauthors = Nau F, Yu B, Martin D, Nichols CD | title = Serotonin 5-HT<sub>2A</sub> receptor activation blocks TNF-α mediated inflammation in vivo | journal = PLOS One | volume = 8 | issue = 10 | pages = e75426 | year = 2013 | pmid = 24098382 | pmc = 3788795 | doi = 10.1371/journal.pone.0075426 }}</ref>
* Activation of the 5-HT<sub>2A</sub> receptor in hypothalamus causes increases in hormonal levels of [[oxytocin]], [[prolactin]], [[ACTH]], [[corticosterone]], and [[renin]].<ref>{{cite journal | vauthors = Van de Kar LD, Javed A, Zhang Y, Serres F, Raap DK, Gray TS | title = 5-HT<sub>2A</sub> receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells | journal = The Journal of Neuroscience | volume = 21 | issue = 10 | pages = 3572–9 | date = May 2001 | pmid = 11331386 }}</ref><ref>{{cite journal | vauthors = Zhang Y, Damjanoska KJ, Carrasco GA, Dudas B, D'Souza DN, Tetzlaff J, Garcia F, Hanley NR, Scripathirathan K, Petersen BR, Gray TS, Battaglia G, Muma NA, Van de Kar LD | title = Evidence that 5-HT<sub>2A</sub> receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (-)DOI | journal = The Journal of Neuroscience | volume = 22 | issue = 21 | pages = 9635–42 | date = November 2002 | pmid = 12417689 | doi =  }}</ref>
* Role in memory and learning<ref name="pmid16277612"/><ref name="pmid14557608">{{cite journal | vauthors = Harvey JA | title = Role of the serotonin 5-HT(2A) receptor in learning | journal = Learning & Memory | volume = 10 | issue = 5 | pages = 355–62 | year = 2003 | pmid = 14557608 | pmc = 218001 | doi = 10.1101/lm.60803 }}</ref><ref name="pmid11923449">{{cite journal | vauthors = Williams GV, Rao SG, Goldman-Rakic PS, Foresta M, Ropolo M, Degan P, Pettinati I, Kow YW, Damonte G, Poggi A, Frosina G | title = Defective repair of 5-hydroxy-2'-deoxycytidine in Cockayne syndrome cells and its complementation by Escherichia coli formamidopyrimidine DNA glycosylase and endonuclease III | journal = Free Radical Biology & Medicine | volume = 48 | issue = 5 | pages = 681–90 | date = March 2010 | pmid = 11923449 <!--| doi = 20026203--> | doi = 10.1016/j.freeradbiomed.2009.12.007 }}</ref>

== Ligands ==

=== Agonists ===
Activation of the 5-HT<sub>2A</sub> [[receptor (biochemistry)|receptor]] is necessary for the effects of the "classic" [[psychedelic drug|psychedelics]] like [[LSD]], [[psilocin]] and [[mescaline]], which act as full or partial [[agonists]] at this receptor, and represent the three main classes of 5-HT<sub>2A</sub> agonists, the [[ergoline]]s, [[tryptamine]]s and [[phenethylamine]]s, respectively. A very large family of derivatives from these three classes has been developed, and their [[structure-activity relationship]]s have been extensively researched.<ref>{{cite journal | vauthors = Nichols DE | title = Hallucinogens | journal = Pharmacology & Therapeutics | volume = 101 | issue = 2 | pages = 131–81 | date = February 2004 | pmid = 14761703 | doi = 10.1016/j.pharmthera.2003.11.002 }}</ref><ref name="pmid18666267">{{cite journal | vauthors = Blaazer AR, Smid P, Kruse CG | title = Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors | journal = ChemMedChem | volume = 3 | issue = 9 | pages = 1299–309 | date = September 2008 | pmid = 18666267 | doi = 10.1002/cmdc.200800133 }}</ref> Agonists acting at  5-HT<sub>2A</sub> receptors located on the [[apical dendrite]]s of [[pyramidal cell]]s within regions of the [[prefrontal cortex]] are believed to mediate hallucinogenic activity. Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the [[GPCR oligomer|receptor heterodimer]] 5-HT<sub>2A</sub>–[[Metabotropic glutamate receptor 2|mGlu2]] and not by [[monomer]]ic 5-HT<sub>2A</sub> receptors.<ref>{{cite journal | vauthors = Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuéllar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, López-Giménez JF, Meana JJ, Benson DL, González-Maeso J | title = Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT<sub>2A</sub>·mGlu2) receptor heteromerization and its psychoactive behavioral function | journal = The Journal of Biological Chemistry | volume = 287 | issue = 53 | pages = 44301–19 | date = December 2012 | pmid = 23129762 | pmc = 3531745 | doi = 10.1074/jbc.M112.413161 }}</ref><ref>{{cite journal | vauthors = González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC | title = Identification of a serotonin/glutamate receptor complex implicated in psychosis | journal = Nature | volume = 452 | issue = 7183 | pages = 93–7 | date = March 2008 | pmid = 18297054 | pmc = 2743172 | doi = 10.1038/nature06612 }}</ref><ref name="ReferenceA"/>  Agonists enhance dopamine in PFC,<ref name="pmid16277612"/> enhance memory and play an active role in attention and learning.<ref name="pmid17124621">{{cite journal | vauthors = Wingen M, Kuypers KP, Ramaekers JG | title = The role of 5-HT1a and 5-HT<sub>2A</sub> receptors in attention and motor control: a mechanistic study in healthy volunteers | journal = Psychopharmacology | volume = 190 | issue = 3 | pages = 391–400 | date = February 2007 | pmid = 17124621 | doi = 10.1007/s00213-006-0614-x }}</ref><ref name="pmid17092965">{{cite journal | vauthors = Wingen M, Kuypers KP, Ramaekers JG | title = Selective verbal and spatial memory impairment after 5-HT1A and 5-HT<sub>2A</sub> receptor blockade in healthy volunteers pre-treated with an SSRI | journal = Journal of Psychopharmacology | volume = 21 | issue = 5 | pages = 477–85 | date = July 2007 | pmid = 17092965 | doi = 10.1177/0269881106072506 }}</ref>

==== Full agonists ====
* [[25I-NBOH]] and its 2-methoxy-analog [[25I-NBOMe]]<ref name="pmid17000863">{{cite journal | vauthors = Braden MR, Parrish JC, Naylor JC, Nichols DE | title = Molecular interaction of serotonin 5-HT<sub>2A</sub> receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists | journal = Molecular Pharmacology | volume = 70 | issue = 6 | pages = 1956–64 | date = December 2006 | pmid = 17000863 | doi = 10.1124/mol.106.028720 }}</ref>
* [[Fluorine-18|<sup>18</sup>F]] [[FECIMBI-36]], [[radiolabelled]] agonist ligand for mapping 5-HT<sub>2A</sub> / 5-HT<sub>2C</sub> receptor distribution <ref>Prabhakaran J, Solingapuram Sai KK, Zanderigo F, Rubin-Falcone H, Jorgensen MJ, Kaplan JR, Tooke KI, Mintz A, Mann JJ, Kumar JS. In vivo evaluation of [18F]FECIMBI-36, an agonist 5-HT<sub>2A</sub>/2C receptor PET radioligand in nonhuman primate. ''Bioorg Med Chem Lett''. 2017 Jan 1;27(1):21-23. doi: 10.1016/j.bmcl.2016.11.043. {{PMID|27889455}}</ref>
* [[TCB-2]]<ref name="pmid16970404">{{cite journal | vauthors = McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE | title = 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT<sub>2A</sub> receptor agonists | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 19 | pages = 5794–803 | date = September 2006 | pmid = 16970404 | doi = 10.1021/jm060656o }}</ref>
* [[Mexamine]] is a full agonist to several serotonin receptors.
* [[O-4310]], 5-HT<sub>2A</sub> selective, claimed to have 100x selectivity over 5-HT<sub>2C</sub> and be inactive at 5-HT<sub>2B</sub>
* [[PHA-57378]], dual 5-HT<sub>2A</sub> / 5-HT<sub>2C</sub> agonist, anxiolytic effects in animal studies.<ref name="pmid12824036">{{cite journal | vauthors = Ennis MD, Hoffman RL, Ghazal NB, Olson RM, Knauer CS, Chio CL, Hyslop DK, Campbell JE, Fitzgerald LW, Nichols NF, Svensson KA, McCall RB, Haber CL, Kagey ML, Dinh DM | title = 2,3,4,5-tetrahydro- and 2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indoles: new templates for 5-HT(2C) agonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 13 | issue = 14 | pages = 2369–72 | date = July 2003 | pmid = 12824036 | doi = 10.1016/S0960-894X(03)00403-7 }}</ref>
* [[25B-NBOMe]] Also known as Cimbi-36; used as a [[Positron emission tomography|PET]] imaging tool for visualizing the 5-HT<sub>2A</sub> receptor<ref name=":0">{{cite journal | vauthors = Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, Jørgensen LM, Hansen M, Baandrup AO, Bache S, Svarer C, Kristensen JL, Gillings N, Madsen J, Knudsen GM | title = Serotonin 2A receptor agonist binding in the human brain with [¹¹C]Cimbi-36 | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 34 | issue = 7 | pages = 1188–96 | date = July 2014 | pmid = 24780897 | doi = 10.1038/jcbfm.2014.68 | pmc = 4083382 }}</ref>

==== Partial agonists ====
* [[25C-NBOMe]]
* [[Bromo-DragonFLY]]<ref name="pmid11300881">{{cite journal | vauthors = Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE | title = Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 6 | pages = 1003–10 | date = March 2001 | pmid = 11300881 | doi = 10.1021/jm000491y }}</ref>
* [[Methysergide]], a congener of [[methylergonovine]], used in treatment of [[migraine]] blocks 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors, but sometimes acts as partial agonist, in some preparations.
* [[OSU-6162]] acts as a partial agonist at both 5-HT<sub>2A</sub> and [[dopamine D2 receptor|dopamine D<sub>2</sub> receptors]]
* [[25CN-NBOH]], 100x selectivity for 5-HT<sub>2A</sub> over 5-HT<sub>2C</sub>, 46x selectivity over 5-HT<sub>2B</sub>.<ref>[https://docs.google.com/open?id=0BwXelgjm5BeEaEJJU0lPa1NnaGM Martin Hansen PhD. Design and Synthesis of Selective Serotonin Receptor Agonists for Positron Emission Tomography Imaging of the Brain. University of Copenhagen, 2011.]</ref>
* [[Juncosamine]], is a structurally constrained derivative of [[25B-NBOMe]], which acts as a potent partial agonist with 124x selectivity for 5-HT<sub>2A</sub> over 5-HT<sub>2C</sub>, making it the most selective agonist ligand identified to date.<ref>{{cite journal | vauthors = Juncosa JI, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, Marona-Lewicka D, Lill MA, Nichols DE | title = Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT<sub>2A</sub> serotonin receptor agonist ligands | journal = ACS Chemical Neuroscience | volume = 4 | issue = 1 | pages = 96–109 | date = January 2013 | pmid = 23336049 | pmc =  3547484| doi = 10.1021/cn3000668 }}</ref>
* [[Efavirenz]], an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT<sub>2A</sub>.<ref>{{cite journal | vauthors = Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA | title = The HIV antiretroviral drug efavirenz has LSD-like properties | journal = Neuropsychopharmacology | volume = 38 | issue = 12 | pages = 2373–84 | date = November 2013 | pmid = 23702798 | pmc = 3799056 | doi = 10.1038/npp.2013.135 }}</ref>
* [[Mefloquine]], an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT<sub>2A</sub> and/or 5-HT<sub>2C</sub> receptors.<ref>{{cite journal | vauthors = Janowsky A, Eshleman AJ, Johnson RA, Wolfrum KM, Hinrichs DJ, Yang J, Zabriskie TM, Smilkstein MJ, Riscoe MK | title = Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro | journal = Psychopharmacology | volume = 231 | issue = 14 | pages = 2771–83 | date = July 2014 | pmid = 24488404 | pmc = 4097020 | doi = 10.1007/s00213-014-3446-0 }}</ref>
* [[Lisuride]], an antiparkinson [[dopamine agonist]] of the [[ergoline]] class, that is also a dual 5-HT<sub>2A</sub> / 5-HT<sub>2C</sub> agonist<ref name="pmid9600588">{{cite journal | vauthors = Egan CT, Herrick-Davis K, Miller K, Glennon RA, Teitler M | title = Agonist activity of LSD and lisuride at cloned 5HT<sub>2A</sub> and 5HT2C receptors | journal = Psychopharmacology | volume = 136 | issue = 4 | pages = 409–14 | date = April 1998 | pmid = 9600588 | doi = 10.1007/s002130050585 }}</ref> and 5-HT<sub>2B</sub> antagonist.<ref name="pmid16614540">{{cite journal | vauthors = Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, Latté KP, Palla D, Schurad B | title = Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis | journal = Clinical Neuropharmacology | volume = 29 | issue = 2 | pages = 80–6 | year = 2006 | pmid = 16614540 | doi = 10.1097/00002826-200603000-00005 }}</ref>
* [[2,5-Dimethoxy-4-iodoamphetamine|(R)-DOI]], traditionally the most common 5-HT<sub>2A</sub> reference agonist used in research<ref>{{cite journal | vauthors = Canal CE, Morgan D | title = Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model | journal = Drug Testing and Analysis | volume = 4 | issue = 7-8 | pages = 556–76 | date = July 2012 | pmid = 22517680 | pmc = 3722587 | doi = 10.1002/dta.1333 }}</ref>

==== Peripherally selective agonists ====
One effect of 5-HT<sub>2A</sub> receptor activation is a reduction in intraocular pressure, and so 5-HT<sub>2A</sub> agonists can be useful for the treatment of [[glaucoma]]. This has led to the development of compounds such as [[AL-34662]] that are hoped to reduce pressure inside the eyes but without crossing the [[blood–brain barrier]] and producing hallucinogenic side effects.<ref name="pmid17341144">{{cite journal | vauthors = Sharif NA, McLaughlin MA, Kelly CR | title = AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist | journal = Journal of Ocular Pharmacology and Therapeutics | volume = 23 | issue = 1 | pages = 1–13 | date = February 2007 | pmid = 17341144 | doi = 10.1089/jop.2006.0093 }}</ref> Animal studies with this compound showed it to be free of hallucinogenic effects at doses up to 30&nbsp;mg/kg, although several of its more lipophilic analogues did produce the [[head-twitch response]] known to be characteristic of hallucinogenic effects in rodents.<ref name="pmid16392816">{{cite journal | vauthors = May JA, Dantanarayana AP, Zinke PW, McLaughlin MA, Sharif NA | title = 1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity | journal = Journal of Medicinal Chemistry | volume = 49 | issue = 1 | pages = 318–28 | date = January 2006 | pmid = 16392816 | doi = 10.1021/jm050663x }}</ref>

=== Silent antagonists ===
* [[Trazodone]] is a potent 5-HT<sub>2A</sub> antagonist, as well as an antagonist on other serotonin receptors.
* [[Mirtazapine]] is a 5-HT<sub>2A</sub>, 5-HT<sub>2C</sub>, and 5-HT<sub>3</sub> antagonist. Mirtazapine also has an antagonistic effect on H<sub>1</sub> histamine receptors. Because of its wide spectrum of serotonergic receptor inhibition, Mirtazapine exhibits an agonistic effect on 5-HT<sub>1A</sub> receptors by funneling more serotonin to them. Mirtazapine is used as an antidepressant in patients dealing with insomnia and weight loss.
* Although [[ergot]] alkaloids are mostly nonspecific 5-HT receptor antagonists, a few ergot derivatives such as [[metergoline]] bind preferentially to members of the 5-HT<sub>2</sub> receptor family.
* The discovery of [[ketanserin]] was a landmark in the pharmacology of 5-HT<sub>2</sub> receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well-known antihypertensive action through 5-HT<sub>2</sub> receptor family, but through its high affinity for alpha<sub>1</sub> adrenergic receptors. It also has high affinity for H<sub>1</sub> histaminergic receptors equal to that at 5-HT<sub>2A</sub> receptors.  Compounds chemically related to ketanserin such as [[ritanserin]] are more selective 5-HT<sub>2A</sub> receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT<sub>2A</sub> receptor antagonists, also potently inhibits 5-HT<sub>2C</sub> receptors.
* [[Nefazodone]] operates by blocking post-synaptic serotonin type-2A receptors and to a lesser extent by inhibiting pre-synaptic serotonin and norepinephrine (noradrenaline) reuptake.
* [[Atypical antipsychotic]] drugs like [[clozapine]], [[olanzapine]], [[quetiapine]], [[risperidone]] and [[asenapine]] are relatively potent antagonists of 5-HT<sub>2A</sub> as are some of the lower potency old generation/typical antipsychotics. Other antagonists are [[MDL-100,907]] (prototype of another new series of 5-HT<sub>2A</sub> antagonists) and [[cyproheptadine]].
* [[Pizotifen]] is a non-selective antagonist.<ref name="Rang187">{{cite book|vauthors = Rang HP|title=Pharmacology|publisher=Churchill Livingstone|location=Edinburgh|year=2003|pages=|isbn=0-443-07145-4|oclc=|doi=}} Page 187</ref>
* [[LY-367,265]] - dual 5-HT<sub>2A</sub> antagonist / SSRI with antidepressant effects
* 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).<ref name="pmid18282705">{{cite journal | vauthors = Shireman BT, Dvorak CA, Rudolph DA, Bonaventure P, Nepomuceno D, Dvorak L, Miller KL, Lovenberg TW, Carruthers NI | title = 2-Alkyl-4-aryl-pyrimidine fused heterocycles as selective 5-HT<sub>2A</sub> antagonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 6 | pages = 2103–8 | date = March 2008 | pmid = 18282705 | doi = 10.1016/j.bmcl.2008.01.090 }}</ref>
* [[9-Aminomethyl-9,10-dihydroanthracene|AMDA]] and related derivatives are another family of selective 5-HT<sub>2A</sub> antagonists.<ref name="pmid10513561">{{cite journal | vauthors = Westkaemper RB, Runyon SP, Bondarev ML, Savage JE, Roth BL, Glennon RA | title = 9-(Aminomethyl)-9,10-dihydroanthracene is a novel and unlikely 5-HT<sub>2A</sub> receptor antagonist | journal = European Journal of Pharmacology | volume = 380 | issue = 1 | pages = R5-7 | date = September 1999 | pmid = 10513561 | doi = 10.1016/S0014-2999(99)00525-7 }}</ref><ref name="pmid12052195">{{cite journal | vauthors = Westkaemper RB, Glennon RA | title = Application of ligand SAR, receptor modeling and receptor mutagenesis to the discovery and development of a new class of 5-HT(2A) ligands | journal = Current Topics in Medicinal Chemistry | volume = 2 | issue = 6 | pages = 575–98 | date = June 2002 | pmid = 12052195 | doi = 10.2174/1568026023393741 }}</ref><ref name="pmid14660041">{{cite journal | vauthors = Peddi S, Roth BL, Glennon RA, Westkaemper RB | title = Spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine-a structurally unique tetracyclic 5-HT<sub>2A</sub> receptor antagonist | journal = European Journal of Pharmacology | volume = 482 | issue = 1-3 | pages = 335–7 | date = December 2003 | pmid = 14660041 | doi = 10.1016/j.ejphar.2003.09.059 }}</ref><ref name="pmid18847250">{{cite journal | vauthors = Runyon SP, Mosier PD, Roth BL, Glennon RA, Westkaemper RB | title = Potential modes of interaction of 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives with the 5-HT<sub>2A</sub> receptor: a ligand structure-affinity relationship, receptor mutagenesis and receptor modeling investigation | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 21 | pages = 6808–28 | date = November 2008 | pmid = 18847250 | pmc = 3088499 | doi = 10.1021/jm800771x }}</ref><ref name="pmid17314044">{{cite journal | vauthors = Wilson KJ, van Niel MB, Cooper L, Bloomfield D, O'Connor D, Fish LR, MacLeod AM | title = 2,5-Disubstituted pyridines: the discovery of a novel series of 5-HT<sub>2A</sub> ligands | journal = Bioorganic & Medicinal Chemistry Letters | volume = 17 | issue = 9 | pages = 2643–8 | date = May 2007 | pmid = 17314044 | doi = 10.1016/j.bmcl.2007.01.098 }}</ref>
* [[Typical antipsychotics]] such as [[Haloperidol]] and [[Chlorpromazine]]
* [[Hydroxyzine]] (Atarax)
* [[5-MeO-NBpBrT]]
* [[Niaprazine]]

=== Inverse agonists ===
* [[AC-90179]] - potent and selective [[inverse agonist]] at 5-HT<sub>2A</sub>, also 5-HT<sub>2C</sub> antagonist.<ref name="pmid11561089">{{cite journal | vauthors = Weiner DM, Burstein ES, Nash N, Croston GE, Currier EA, Vanover KE, Harvey SC, Donohue E, Hansen HC, Andersson CM, Spalding TA, Gibson DF, Krebs-Thomson K, Powell SB, Geyer MA, Hacksell U, Brann MR | title = 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 299 | issue = 1 | pages = 268–76 | date = October 2001 | pmid = 11561089 | doi =  }}</ref><ref name="pmid15102927">{{cite journal | vauthors = Vanover KE, Harvey SC, Son T, Bradley SR, Kold H, Makhay M, Veinbergs I, Spalding TA, Weiner DM, Andersson CM, Tolf BR, Brann MR, Hacksell U, Davis RE | title = Pharmacological characterization of AC-90179 [2-(4-methoxyphenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide hydrochloride]: a selective serotonin 2A receptor inverse agonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 310 | issue = 3 | pages = 943–51 | date = September 2004 | pmid = 15102927 | doi = 10.1124/jpet.104.066688 }}</ref>
* [[Nelotanserin]] (APD-125) - selective 5-HT<sub>2A</sub> inverse agonist developed by [[Arena Pharmaceuticals]] for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials.<ref>{{cite journal | vauthors = Rosenberg R, Seiden DJ, Hull SG, Erman M, Schwartz H, Anderson C, Prosser W, Shanahan W, Sanchez M, Chuang E, Roth T | title = APD125, a selective serotonin 5-HT(2A) receptor inverse agonist, significantly improves sleep maintenance in primary insomnia | journal = Sleep | volume = 31 | issue = 12 | pages = 1663–71 | date = December 2008 | pmid = 19090322 | pmc = 2603489 | doi = 10.1093/sleep/31.12.1663 }}</ref>
* [[Eplivanserin]] ([[Sanofi Aventis]]), a sleeping pill that reached phase II trials (but for which the application for approval was withdrawn), acts as a selective 5-HT<sub>2A</sub> inverse agonist.
* [[Pimavanserin|Pimavanserin (ACP-103)]] - more selective than AC-90179, orally active, antipsychotic ''in vivo'', now FDA approved for the treatment of hallucinations and delusions associated with Parkinson’s disease.<ref name="pmid16469866">{{cite journal | vauthors = Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE | title = Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 317 | issue = 2 | pages = 910–8 | date = May 2006 | pmid = 16469866 | doi = 10.1124/jpet.105.097006 }}</ref><ref name="pmid17519387">{{cite journal | vauthors = Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW | title = ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 322 | issue = 2 | pages = 862–70 | date = August 2007 | pmid = 17519387 | doi = 10.1124/jpet.107.121715 }}</ref><ref name="pmid18534670">{{cite journal | vauthors = Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD | title = A 5-HT<sub>2A</sub> receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model | journal = Pharmacology Biochemistry and Behavior | volume = 90 | issue = 4 | pages = 540–4 | date = October 2008 | pmid = 18534670 | pmc = 2806670 | doi = 10.1016/j.pbb.2008.04.010 }}</ref><ref name="pmid19040345">{{cite journal | vauthors = Abbas A, Roth BL | title = Pimavanserin tartrate: a 5-HT<sub>2A</sub> inverse agonist with potential for treating various neuropsychiatric disorders | journal = Expert Opinion on Pharmacotherapy | volume = 9 | issue = 18 | pages = 3251–9 | date = December 2008 | pmid = 19040345 | doi = 10.1517/14656560802532707 }}</ref><ref>http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm498442.htm</ref>
* [[Volinanserin]]

=== Functional selectivity ===
5-HT<sub>2A</sub>-receptor [[Ligand (biochemistry)|ligands]] may differentially activate the [[signal transduction|transductional pathways]] ([[#Signalling Cascade|see above]]). Studies evaluated the activation of two [[Effector (biology)|effectors]], [[Phospholipase C|PLC]] and [[Phospholipase A2|PLA2]], by means of their [[second messenger]]s. Compounds displaying more pronounced [[functional selectivity]] are [[Dimethoxyamphetamine#2,5-DMA|2,5-DMA]] and [[2C-N]]. The former induces [[Inositol triphosphate|IP]] accumulation without activating the PLA2 mediated response, while the latter elicits [[Arachidonic acid|AA]] release without activating the PLC mediated response.<!--other pathways were not examined in the reference--><ref name="pmid17337633">{{cite journal | vauthors = Moya PR, Berg KA, Gutiérrez-Hernandez MA, Sáez-Briones P, Reyes-Parada M, Cassels BK, Clarke WP | title = Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 321 | issue = 3 | pages = 1054–61 | date = June 2007 | pmid = 17337633 | doi = 10.1124/jpet.106.117507 }}</ref><br />
[[File:2,5-dma.png|120px]]
[[File:2C-N.png|130px]]

Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT<sub>2A</sub> agonists that produce [[headshake response|headshakes]] in the [[mouse]] and those that do not, such as [[lisuride]], as these agents are also non-hallucinogenic in humans despite being active 5-HT<sub>2A</sub> agonists.<ref name="pmid17270739">{{cite journal | vauthors = González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA | title = Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior | journal = Neuron | volume = 53 | issue = 3 | pages = 439–52 | date = February 2007 | pmid = 17270739 | doi = 10.1016/j.neuron.2007.01.008 }}</ref><ref name="pmid18703043">{{cite journal | vauthors = Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I | title = Agonist-directed trafficking of signalling at serotonin 5-HT<sub>2A</sub>, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells | journal = European Journal of Pharmacology | volume = 594 | issue = 1-3 | pages = 32–8 | date = October 2008 | pmid = 18703043 | doi = 10.1016/j.ejphar.2008.07.040 }}</ref>
One known example of differences in signal transduction is between the two 5-HT<sub>2A</sub> agonists serotonin and [[2,5-dimethoxy-4-iodoamphetamine|DOI]] that involves differential recruitment of intracellular proteins called β-[[arrestin]]s, more specifically [[arrestin beta 2]].<ref name="pmid18195357">{{cite journal | vauthors = Schmid CL, Raehal KM, Bohn LM | title = Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 3 | pages = 1079–84 | date = January 2008 | pmid = 18195357 | pmc = 2242710 | doi = 10.1073/pnas.0708862105 }}</ref><ref name="pmid18195368">{{cite journal | vauthors = Abbas A, Roth BL | title = Arresting serotonin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 3 | pages = 831–2 | date = January 2008 | pmid = 18195368 | pmc = 2242676 | doi = 10.1073/pnas.0711335105 }}</ref>

=== Role of lipophilicity ===
A set of ligands were evaluated. For agonists, a highly significant linear correlation was observed between [[Dissociation constant#Protein-ligand binding|binding affinity]] and [[lipophilicity]]. For ligands exhibiting partial agonist or antagonist properties, the lipophilicity was consistently higher than would be expected for an agonist of comparable affinity.<ref name="pmid18296055">{{cite journal | vauthors = Parker MA, Kurrasch DM, Nichols DE | title = The role of lipophilicity in determining binding affinity and functional activity for 5-HT<sub>2A</sub> receptor ligands | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 8 | pages = 4661–9 | date = April 2008 | pmid = 18296055 | pmc = 2442558 | doi = 10.1016/j.bmc.2008.02.033 }}</ref>

== Genetics ==
[[File:Chromosome 13.jpeg|thumb|right|[[Chromosome 13|Chromosome&nbsp;13]].]]
The 5-HT<sub>2A</sub> receptors is coded by the ''HTR2A'' gene.
In humans the gene is located on [[chromosome 13]].
The gene has previously been called just HTR2 until the description of two related genes ''[[HTR2B]]'' and ''[[HTR2C]]''.
Several interesting [[polymorphism (biology)|polymorphisms]]  have been identified for HTR2A:
[[A-1438G]] ([[rs6311]]),
[[C102T]] ([[rs6313]]) and
[[His452Tyr]] ([[rs6314]]).
Many more polymorphisms exist for the gene.
A 2006 paper listed 255.<ref name="pmid16882651">{{cite journal | vauthors = Bonis J, Furlong LI, Sanz F | title = OSIRIS: a tool for retrieving literature about sequence variants | journal = Bioinformatics | volume = 22 | issue = 20 | pages = 2567–9 | date = October 2006 | pmid = 16882651 | doi = 10.1093/bioinformatics/btl421 | quote = Supplementary material to article }}</ref> 
* {{cite journal | vauthors = Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE | title = Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 6 | pages = 1003–10 | date = March 2001 | pmid = 11300881 | doi = 10.1021/jm000491y }}</ref>

=== Associations with psychiatric disorders ===
Several studies have seen links between the -1438G/A polymorphism and [[mood disorders]], such as [[bipolar disorder]]<ref name="pmid11702051">{{cite journal | vauthors = Chee IS, Lee SW, Kim JL, Wang SK, Shin YO, Shin SC, Lee YH, Hwang HM, Lim MR | title = 5-HT<sub>2A</sub> receptor gene promoter polymorphism -1438A/G and bipolar disorder | journal = Psychiatric Genetics | volume = 11 | issue = 3 | pages = 111–4 | date = September 2001 | pmid = 11702051 | doi = 10.1097/00041444-200109000-00001 }}</ref>
and [[major depressive disorder]].<ref name="pmid14730199">{{cite journal | vauthors = Choi MJ, Lee HJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS | title = Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene | journal = Neuropsychobiology | volume = 49 | issue = 1 | pages = 38–41 | year = 2004 | pmid = 14730199 | doi = 10.1159/000075337 }}</ref>
A weak link with an [[odds ratio]] of 1.3 has been found between the T102C polymorphism and [[schizophrenia]].<ref name="pmid8622505">{{cite journal | vauthors = Williams J, Spurlock G, McGuffin P, Mallet J, Nöthen MM, Gill M, Aschauer H, Nylander PO, Macciardi F, Owen MJ | title = Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) Group | journal = Lancet | volume = 347 | issue = 9011 | pages = 1294–6 | date = May 1996 | pmid = 8622505 | doi = 10.1016/s0140-6736(96)90939-3 }}</ref>
This polymorphism has also been studied in relation to [[suicide]] attempts, with a study finding excess of the C/C genotypes among the suicide attempters.<ref name="pmid18163387">{{cite journal | vauthors = Vaquero-Lorenzo C, Baca-Garcia E, Diaz-Hernandez M, Perez-Rodriguez MM, Fernandez-Navarro P, Giner L, Carballo JJ, Saiz-Ruiz J, Fernandez-Piqueras J, Baldomero EB, de Leon J, Oquendo MA | title = Association study of two polymorphisms of the serotonin-2A receptor gene and suicide attempts | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 147B | issue = 5 | pages = 645–9 | date = July 2008 | pmid = 18163387 | doi = 10.1002/ajmg.b.30642 }}</ref> A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.<!--

--><ref name="SZgene">[http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=293 Gene Overview of All Published Schizophrenia-Association Studies for HTR2A] {{webarchive|url=https://web.archive.org/web/20090221125658/http://schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=293 |date=21 February 2009 }} - [[SzGene]] database at [[Schizophrenia Research Forum]].</ref>

These individual studies may, however, not give a full picture: A review from 2007 looking at the effect of different SNPs reported in separate studies stated that "genetic association studies &#91;of ''HTR2A'' gene variants with psychiatric disorders&#93; report conflicting and generally negative results" with no involvement, small or a not replicated role for the genetic variant of the gene.<ref name="pmid17691947">{{cite journal | vauthors = Serretti A, Drago A, De Ronchi D | title = HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies | journal = Current Medicinal Chemistry | volume = 14 | issue = 19 | pages = 2053–69 | year = 2007 | pmid = 17691947 | doi = 10.2174/092986707781368450 }}</ref>

==== Treatment response ====
One study has found that genetic variations between individuals in the HTR2A gene may to some extent account for the difference in outcome of antidepressant treatment, so that patients suffering from [[major depressive disorder]] and treated with [[citalopram]] may benefit more than others if they have one particular genotype.<ref name="pmid16642436">{{cite journal | vauthors = McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJ, Papanicolaou GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H | title = Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment | journal = American Journal of Human Genetics | volume = 78 | issue = 5 | pages = 804–14 | date = May 2006 | pmid = 16642436 | pmc = 1474035 | doi = 10.1086/503820 }}</ref>
In this study 768 [[single nucleotide polymorphism]] (SNP) across 68 genes were investigated and a SNP—termed [[rs7997012]]—in the second [[intron]] of the HTR2A gene showed significant association with treatment outcome.

Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.<ref name="pmid17898344">{{cite journal | vauthors = Laje G, Paddock S, Manji H, Rush AJ, Wilson AF, Charney D, McMahon FJ | title = Genetic markers of suicidal ideation emerging during citalopram treatment of major depression | journal = The American Journal of Psychiatry | volume = 164 | issue = 10 | pages = 1530–8 | date = October 2007 | pmid = 17898344 | doi = 10.1176/appi.ajp.2007.06122018 }}</ref><ref name="pmid17949692">{{cite journal | vauthors = Laje G, McMahon FJ | title = The pharmacogenetics of major depression: past, present, and future | journal = Biological Psychiatry | volume = 62 | issue = 11 | pages = 1205–7 | date = December 2007 | pmid = 17949692 | doi = 10.1016/j.biopsych.2007.09.016 }}</ref>

One study has also linked abnormal 5-HT<sub>2A</sub> polymorphisms which may enhance receptor activity with [[Chronic Fatigue Syndrome]].<ref>{{cite journal | vauthors = Smith AK, Dimulescu I, Falkenberg VR, Narasimhan S, Heim C, Vernon SD, Rajeevan MS | title = Genetic evaluation of the serotonergic system in chronic fatigue syndrome | journal = Psychoneuroendocrinology | volume = 33 | issue = 2 | pages = 188–97 | date = February 2008 | pmid = 18079067 | pmc =  | doi = 10.1016/j.psyneuen.2007.11.001 }}</ref>

== Neuroimaging ==
The 5-HT<sub>2A</sub> receptors may be imaged with [[PET-scanner]]s using the fluorine-18-[[altanserin]]<ref name="pmid1744713">{{cite journal | vauthors = Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L | title = Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats | journal = Journal of Nuclear Medicine | volume = 32 | issue = 12 | pages = 2266–72 | date = December 1991 | pmid = 1744713 }}</ref>
, MDL&nbsp;100,907<ref name="pmid8602111">{{cite journal | vauthors = Lundkvist C, Halldin C, Ginovart N, Nyberg S, Swahn CG, Carr AA, Brunner F, Farde L | title = [11C]MDL 100907, a radioligland for selective imaging of 5-HT(2A) receptors with positron emission tomography | journal = Life Sciences | volume = 58 | issue = 10 | pages = PL 187–92 | year = 1996 | pmid = 8602111 | doi = 10.1016/0024-3205(96)00013-6 }}</ref>
or [<sup>11</sup>C]Cimbi-36<ref name=":0" /><ref name=":1">{{cite journal | vauthors = Johansen A, Hansen HD, Svarer C, Lehel S, Leth-Petersen S, Kristensen JL, Gillings N, Knudsen GM | title = 11C]Cimbi-36 labeled in two positions | journal = Journal of Cerebral Blood Flow and Metabolism | volume = Epub | pages = 271678X17746179 | date = January 2017 | pmid = 29215308 | doi = 10.1177/0271678x17746179 }}</ref> [[radioligand]]s that binds to the neuroreceptor, e.g.,
one study reported a ''reduced'' binding of altanserin particularly in the [[hippocampus]] in patients with [[major depressive disorder]].<ref name="pmid14744461">{{cite journal | vauthors = Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang Y, Snyder AZ | title = Decreased hippocampal 5-HT<sub>2A</sub> receptor binding in major depressive disorder: in vivo measurement with [18F]altanserin positron emission tomography | journal = Biological Psychiatry | volume = 55 | issue = 3 | pages = 217–24 | date = February 2004 | pmid = 14744461 | doi = 10.1016/j.biopsych.2003.08.015 }}</ref>
Another PET study reported ''increased'' altanserin binding in the [[caudate nucleus|caudate nuclei]] in [[obsessive compulsive disorder]] patients compared to a healthy control group.<ref name="pmid15801987">{{cite journal | vauthors = Adams KH, Hansen ES, Pinborg LH, Hasselbalch SG, Svarer C, Holm S, Bolwig TG, Knudsen GM | title = Patients with obsessive-compulsive disorder have increased 5-HT<sub>2A</sub> receptor binding in the caudate nuclei | journal = The International Journal of Neuropsychopharmacology | volume = 8 | issue = 3 | pages = 391–401 | date = September 2005 | pmid = 15801987 | doi = 10.1017/S1461145705005055 }}</ref>

Patients with [[Tourette's syndrome]] have also been scanned and the study found an increased binding of altanserin for patients compared to healthy controls.<ref name="pmid16945163">{{cite journal | vauthors = Haugbøl S, Pinborg LH, Regeur L, Hansen ES, Bolwig TG, Nielsen FA, Svarer C, Skovgaard LT, Knudsen GM | title = Cerebral 5-HT<sub>2A</sub> receptor binding is increased in patients with Tourette's syndrome | journal = The International Journal of Neuropsychopharmacology | volume = 10 | issue = 2 | pages = 245–52 | date = April 2007 | pmid = 16945163 | doi = 10.1017/S1461145706006559 }}</ref> The altanserin uptake decreases with [[aging|age]] reflecting a loss of specific 5-HT<sub>2A</sub> receptors with age.<ref name="pmid9027929">{{cite journal | vauthors = Rosier A, Dupont P, Peuskens J, Bormans G, Vandenberghe R, Maes M, de Groot T, Schiepers C, Verbruggen A, Mortelmans L | title = Visualisation of loss of 5-HT<sub>2A</sub> receptors with age in healthy volunteers using [18F]altanserin and positron emission tomographic imaging | journal = Psychiatry Research | volume = 68 | issue = 1 | pages = 11–22 | date = November 1996 | pmid = 9027929 | doi = 10.1016/S0925-4927(96)02806-5 }}</ref><ref name="pmid9824691">{{cite journal | vauthors = Meltzer CC, Smith G, Price JC, Reynolds CF, Mathis CA, Greer P, Lopresti B, Mintun MA, Pollock BG, Ben-Eliezer D, Cantwell MN, Kaye W, DeKosky ST | title = Reduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction | journal = Brain Research | volume = 813 | issue = 1 | pages = 167–71 | date = November 1998 | pmid = 9824691 | doi = 10.1016/S0006-8993(98)00909-3 }}</ref><ref name="pmid15006678">{{cite journal | vauthors = Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbøl S, Madsen K, Frøkjaer V, Martiny L, Paulson OB, Knudsen GM | title = A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables | journal = NeuroImage | volume = 21 | issue = 3 | pages = 1105–13 | date = March 2004 | pmid = 15006678 | doi = 10.1016/j.neuroimage.2003.10.046 }}</ref>
A study has also found a positive correlation among healthy subjects between altanserin binding and the personality trait [[neuroticism]] as measured by the [[NEO PI-R]] personality questionnaire.<ref name="pmid17884017">{{cite journal | vauthors = Frokjaer VG, Mortensen EL, Nielsen FA, Haugbol S, Pinborg LH, Adams KH, Svarer C, Hasselbalch SG, Holm S, Paulson OB, Knudsen GM | title = Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder | journal = Biological Psychiatry | volume = 63 | issue = 6 | pages = 569–76 | date = March 2008 | pmid = 17884017 | doi = 10.1016/j.biopsych.2007.07.009 }}</ref>

== Role in virus endocytosis ==
5-HT<sub>2A</sub> may be a necessary receptor for [[clathrin]] mediated [[endocytosis]] of the human [[polyoma virus]] called [[JC virus]], the causative agent of [[progressive multifocal leukoencephalopathy]] (PML), that enters cells such as [[oligodendrocyte]]s, [[astrocyte]]s, [[B lymphocytes]], and kidney epithelial cells. These cells need to express both the alpha 2-6–linked [[sialic acid]] component of the 5-HT<sub>2A</sub> receptor in order to endocytose JCV.<ref name="pmid15550673"/>

== References ==
{{Reflist|35em}}

== Further reading ==
* {{cite journal | vauthors = Perez-Aguilar JM, Shan J, LeVine MV, Khelashvili G, Weinstein H | title = A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2 | journal = Journal of the American Chemical Society | volume = 136 | issue = 45 | pages = 16044–54 | date = November 2014 | pmid = 25314362 | pmc = 4235374 | doi = 10.1021/ja508394x }}

== External links ==
* {{cite web| url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2320| title = 5-HT<sub>2A</sub>| access-date =| work = IUPHAR Database of Receptors and Ion Channels| publisher = International Union of Basic and Clinical Pharmacology| pages =}}
* {{MeshName|5-HT<sub>2A</sub>+Receptor}}
* {{UCSC gene info|HTR2A}}

{{G protein-coupled receptors}}
{{Obsessive–compulsive disorder}}
{{Hallucinogens}}
{{Hypnotics and sedatives}}
{{Serotonergics}}

{{Use dmy dates|date=February 2011}}

[[Category:Biology of attention deficit hyperactivity disorder]]
[[Category:Biology of bipolar disorder]]
[[Category:Serotonin receptors]]