5-HT2A receptor

The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR).[5] 5-HT is short for 5-hydroxy-tryptamine, which is serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect[6] on certain areas such as the visual cortex and the orbitofrontal cortex.[7] This receptor was first noted for its importance as a target of 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 ones.

5-HT2A may be a necessary receptor for the spread of the human polyoma virus called the JC virus.[8]

Downregulation of post-synaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and classical antipsychotics. Suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These findings suggest that post-synaptic 5-HT2A overdensity is involved in the pathogenesis of depression.[9]

Paradoxical down-regulation of 5-HT2A receptors can be observed with several 5-HT2A antagonists.[10] Thus, instead of tolerance, reverse-tolerance would be expected from 5-HT2A antagonists. However, there is at least one antagonist at this site which has been shown to up-regulate 5-HT2A receptors.[10][11] Additionally, a couple of other antagonists may have no effect on 5-HT2A receptor number.[12] Nevertheless, upregulation is the exception rather than the rule. Neither tolerance nor rebound is observed in humans with regard to the SWS promoting effects of 5-HT2A antagonists.[13]

HTR2A
5ht2a
Identifiers
AliasesHTR2A, 5-HT2A, HTR2, 5-hydroxytryptamine receptor 2A
External IDsOMIM: 182135 MGI: 109521 HomoloGene: 68073 GeneCards: HTR2A
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001165947
NM_000621

NM_172812

RefSeq (protein)

NP_000612
NP_001159419

NP_766400

Location (UCSC)Chr 13: 46.83 – 46.9 MbChr 14: 74.64 – 74.71 Mb
PubMed search[3][4]
Wikidata

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 could be blocked by morphine, whilst the remainder of the response was inhibited by dibenzyline leading to the naming of M and D receptors respectively. 5-HT2A is thought to correspond to what was originally described as D subtype of 5-HT receptors by Gaddum and Picarelli.[14] 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, 5-HT2 and 5-HT3 receptors, corresponding to high affinity sites from LSD, spiperone and morphine respectively.[15] Later it was shown that the 5-HT2 was very close to 5-HT1C and thus were clubbed together, renaming the 5-HT2 into 5-HT2A. Thus the 5-HT2 receptor family is composed of three separate molecular entities: the 5-HT2A (formerly known as 5-HT2 or D), the 5-HT2B (formerly known as 5-HT2F) and the 5-HT2C (formerly known as 5-HT1C) receptors.[16]

Distribution

5-HT2A is expressed widely throughout the central nervous system (CNS). It is expressed near most of the serotoninergic terminal rich areas, including neocortex (mainly prefrontal, parietal, and somatosensory cortex) and the olfactory tubercle. Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes, working memory, and attention[17][18][19] by enhancing glutamate release followed by a complex range of interactions with the 5-HT1A,[20] GABAA,[21] adenosine A1,[22] AMPA,[23] mGluR2/3,[24] mGlu5,[25] and OX2 receptors.[26][27] In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer,[28] and in the Purkinje cells.[29][30]

In the periphery, it is highly expressed in platelets and many cell types of the cardiovascular system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT2A mRNA expression has been observed in human monocytes.[31]

Signaling cascade

The 5-HT2A receptor is known primarily to couple to the Gαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways. Gαq stimulates phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulate protein kinase C (PKC) activity and Ca2+ release.[32]

There are many additional signal cascade components that include the formation of arachidonic acid through PLA2 activity, activation of phospholipase D, Rho/Rho kinase, and ERK pathway activation initiated by agonist stimulation of the receptor.

Effects

Physiological processes mediated by the receptor include:

Ligands

Agonists

Activation of the 5-HT2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched.[41][42] Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells 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 receptor heterodimer 5-HT2AmGlu2 and not by monomeric 5-HT2A receptors.[43][44][33] Agonists enhance dopamine in PFC,[19] enhance memory and play an active role in attention and learning.[45][46]

Full agonists

  • Agmatine
  • 25I-NBOH and its 2-methoxy-analog 25I-NBOMe[47]
  • 18F FECIMBI-36, radiolabelled agonist ligand for mapping 5-HT2A / 5-HT2C receptor distribution [48]
  • TCB-2[49]
  • Mexamine is a full agonist to several serotonin receptors.
  • O-4310, 5-HT2A selective, claimed to have 100x selectivity over 5-HT2C and be inactive at 5-HT2B
  • PHA-57378, dual 5-HT2A / 5-HT2C agonist, anxiolytic effects in animal studies.[50]
  • 25B-NBOMe Also known as Cimbi-36; used as a PET imaging tool for visualizing the 5-HT2A receptor[51]

Partial agonists

  • 25C-NBOMe
  • 25CN-NBOH, 100x selectivity for 5-HT2A over 5-HT2C, 46x selectivity over 5-HT2B.[52]
  • Bromo-DragonFLY[53]
  • (R)-DOI, traditionally the most common 5-HT2A reference agonist used in research[54]
  • Efavirenz, an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT2A.[55]
  • Juncosamine, is a structurally constrained derivative of 25B-NBOMe, which acts as a potent partial agonist with 124x selectivity for 5-HT2A over 5-HT2C, making it the most selective agonist ligand identified to date.[56]
  • Lisuride, an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT2A / 5-HT2C agonist[57] and 5-HT2B antagonist.[58]
  • Mefloquine, an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT2A and/or 5-HT2C receptors.[59]
  • Methysergide, a congener of methylergonovine, used in treatment of migraine blocks 5-HT2A and 5-HT2C receptors, but sometimes acts as partial agonist, in some preparations.
  • OSU-6162 acts as a partial agonist at both 5-HT2A and dopamine D2 receptors
  • SN-22, partial agonist at all three 5-HT2 subtypes

Peripherally selective agonists

One effect of 5-HT2A receptor activation is a reduction in intraocular pressure, and so 5-HT2A 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.[60] Animal studies with this compound showed it to be free of hallucinogenic effects at doses up to 30 mg/kg, although several of its more lipophilic analogues did produce the head-twitch response known to be characteristic of hallucinogenic effects in rodents.[61]

Silent antagonists

  • Trazodone is a potent 5-HT2A antagonist, as well as an antagonist on other serotonin receptors.
  • Mirtazapine is a 5-HT2A, 5-HT2C, and 5-HT3 antagonist. Mirtazapine also has an antagonistic effect on H1 histamine receptors. Because of its wide spectrum of serotonergic receptor inhibition, Mirtazapine exhibits an agonistic effect on 5-HT1A 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-HT2 receptor family.
  • The discovery of ketanserin was a landmark in the pharmacology of 5-HT2 receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well-known antihypertensive action through 5-HT2 receptor family, but through its high affinity for alpha1 adrenergic receptors. It also has high affinity for H1 histaminergic receptors equal to that at 5-HT2A receptors. Compounds chemically related to ketanserin such as ritanserin are more selective 5-HT2A receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT2A receptor antagonists, also potently inhibits 5-HT2C 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-HT2A as are some of the lower potency old generation/typical antipsychotics. Other antagonists are MDL-100,907 (prototype of another new series of 5-HT2A antagonists) and cyproheptadine.
  • Pizotifen is a non-selective antagonist.[62]
  • LY-367,265 - dual 5-HT2A antagonist / SSRI with antidepressant effects
  • 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).[63]
  • AMDA and related derivatives are another family of selective 5-HT2A antagonists.[64][65][66][67][68]
  • Typical antipsychotics such as Haloperidol and Chlorpromazine
  • Hydroxyzine (Atarax)
  • 5-MeO-NBpBrT
  • Niaprazine

Inverse agonists

  • AC-90179 - potent and selective inverse agonist at 5-HT2A, also 5-HT2C antagonist.[69][70]
  • Nelotanserin (APD-125) - selective 5-HT2A inverse agonist developed by Arena Pharmaceuticals for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials.[71]
  • 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-HT2A inverse agonist.
  • 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.[72][73][74][75][76]
  • Volinanserin

Functional selectivity

5-HT2A-receptor ligands may differentially activate the transductional pathways (see above). Studies evaluated the activation of two effectors, PLC and PLA2, by means of their second messengers. Compounds displaying more pronounced functional selectivity are 2,5-DMA and 2C-N. The former induces IP accumulation without activating the PLA2 mediated response, while the latter elicits AA release without activating the PLC mediated response.[77]

2,5-DMA
2C-N

2,5-DMA
2C-N

Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT2A agonists that produce 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-HT2A agonists.[78][79] One known example of differences in signal transduction is between the two 5-HT2A agonists serotonin and DOI that involves differential recruitment of intracellular proteins called β-arrestins, more specifically arrestin beta 2.[80][81]

Role of lipophilicity

A set of ligands were evaluated. For agonists, a highly significant linear correlation was observed between 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.[82]

Genetics

The 5-HT2A 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 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.[83][84]

Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as bipolar disorder[85] and major depressive disorder.[86] A weak link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia.[87] 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.[88] A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.[89]

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 [of HTR2A gene variants with psychiatric disorders] report conflicting and generally negative results" with no involvement, small or a not replicated role for the genetic variant of the gene.[90]

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.[91] 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.[92][93]

One study has also linked abnormal 5-HT2A polymorphisms which may enhance receptor activity with chronic fatigue syndrome.[94]

Neuroimaging

The 5-HT2A receptors may be imaged with PET-scanners using the fluorine-18-altanserin[95] , MDL 100,907[96] or [11C]Cimbi-36[51][97] radioligands 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.[98] Another PET study reported increased altanserin binding in the caudate nuclei in obsessive compulsive disorder patients compared to a healthy control group.[99]

Patients with Tourette's syndrome have also been scanned and the study found an increased binding of altanserin for patients compared to healthy controls.[100] The altanserin uptake decreases with age reflecting a loss of specific 5-HT2A receptors with age.[101][102][103] 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.[104]

Role in virus endocytosis

5-HT2A 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 oligodendrocytes, astrocytes, B lymphocytes, and kidney epithelial cells. These cells need to express both the alpha 2-6–linked sialic acid component of the 5-HT2A receptor in order to endocytose JCV.[8]

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Further reading

External links

2,5-Dimethoxy-4-amylamphetamine

Dimethoxy-4-amylamphetamine (DOAM) is a lesser-known psychedelic drug and a substituted amphetamine. DOAM was first synthesized by Alexander Shulgin. In his book PiHKAL (Phenethylamines i Have Known And Loved), the minimum dosage is listed as 10 mg, and the duration is unknown. DOAM produces a bare threshold and tenseness. As the 4-alkyl chain length is increased from shorter homologues such as DOM, DOET, DOPR, and DOBU which are all potent hallucinogens, the 5-HT2 binding affinity increases, rising to a maximum with the 4-(n-hexyl) derivative before falling again with even longer chains, but compounds with chain length longer than n-propyl, or with other bulky groups such as isopropyl, t-butyl or γ-phenylpropyl at the 4- position, fail to substitute for hallucinogens in animals or produce hallucinogenic effects in humans, suggesting these have low efficacy and are thus antagonists or weak partial agonists at the 5-HT2A receptor.

2,5-Dimethoxy-4-butylamphetamine

2,5-Dimethoxy-4-butylamphetamine (DOBU) is a lesser-known psychedelic drug and a substituted Amphetamine. DOBU was first synthesized by Alexander Shulgin. In his book PiHKAL (Phenethylamines i Have Known And Loved), only low dosages of 2–3 mg were tested, with the duration simply listed as "very long". DOBU produces paresthesia and difficulty sleeping, but with few other effects. Compared to shorter chain homologues such as DOM, DOET and DOPR which are all potent hallucinogens, DOBU has an even stronger 5-HT2 binding affinity but fails to substitute for hallucinogens in animals or produce hallucinogenic effects in humans, suggesting it has low efficacy and is thus an antagonist or weak partial agonist at the 5-HT2A receptor.

25B-NBOMe

25B-NBOMe (NBOMe-2C-B, Cimbi-36, Nova, BOM 2-CB) is a derivative of the phenethylamine psychedelic 2C-B, discovered in 2004 by Ralf Heim at the Free University of Berlin. It acts as a potent full agonist for the 5HT2A receptor. Anecdotal reports from users suggest 25B-NBOMe to be an active hallucinogen at a dose of as little as 250–500 µg, making it a similar potency to other phenethylamine derived hallucinogens such as Bromo-DragonFLY. Duration of effects lasts about 12–16 hours.The carbon-11 labeled version of this compound ([11C]Cimbi-36) was synthesized and validated as a radioactive tracer for positron emission tomography (PET) in Copenhagen. As a 5-HT2A receptor agonist PET radioligand, [11C]Cimbi-36 was hypothesized to provide a more functional marker of these receptors. Also, [11C]Cimbi-36 is investigated as a potential marker of serotonin release and thus could serve as an indicator of serotonin levels in vivo. [11C]Cimbi-36 is now undergoing clinical trials as a PET-ligand in humans.

25CN-NBOH

25CN-NBOH (or NBOH-2C-CN) is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 by a group of researchers at the University of Copenhagen. This compound is notable as one of the most selective agonist ligands for the 5-HT2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT2A receptor and with 100x selectivity for 5-HT2A over 5-HT2C, and 46x selectivity for 5-HT2A over 5-HT2B. In animal studies, 25CN-NBOH was found to partially substitute for DOI but was considerably weaker at inducing a head-twitch response in mice. Another in vivo evaluation of 25CN-NBOH concluded that "Given its distinct in vitro selectivity for 5-HT2A over non 5-HT2 receptors and its behavioral dynamics, 25CN-NBOH appears to be a powerful tool for dissection of receptor-specific cortical circuit dynamics, including 5-HT2A related psychoactivity."

25I-NB34MD

25I-NB34MD (NB34MD-2C-I) is a derivative of the phenethylamine hallucinogen 2C-I, which acts as a potent partial agonist for the human 5-HT2A receptor, and presumably has similar properties to 2C-I. It has a binding affinity of 0.67nM at the human 5-HT2A receptor, making it several times weaker than its positional isomer 25I-NBMD and a similar potency to 25I-NBF.

5-I-R91150

5-I-R91150 (or R93274) is a compound that acts as a potent and selective antagonist of 5-HT2A receptors. Its main application is as its iodine-123 radiolabeled form, in which it can be used in SPECT scanning in human neuroimaging studies, to examine the distribution of the 5-HT2A receptor subtype in the brain, e.g. with respect to sex and age and in adults with Asperger syndrome or Alzheimer's disease.An alternative 5-HT2A receptor ligand also used in neuroimaging is altanserin.

9-Aminomethyl-9,10-dihydroanthracene

AMDA (9-Aminomethyl-9,10-dihydroanthracene) is an organic compound which acts as a potent and selective antagonist for the 5-HT2A receptor. It has been used to help study the shape of the 5-HT2A protein, and develop a large family of related derivatives with even higher potency and selectivity.

Altanserin

Altanserin is a compound that binds to the 5-HT2A receptor (5-Hydroxytryptamine (serotonin) 2A receptor). Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography (PET) studies of the brain, i.e., studies of the 5-HT2A neuroreceptors. Besides human neuroimaging studies altanserin has also been used in the study of rats.An alternative for PET imaging the 5-HT2A receptor is the

[11C]volinanserin (MDL-100,907) radioligand.

18F-altanserin and 3H-volinanserin have shown very comparable binding.

Both altanserin and MDL 100,907 are 5-HT2A receptor antagonists.

[18F]-setoperone can also be used in PET.

An alternative SPECT radioligand is the [123I]-5-I-R91150 receptor antagonist.A rapid chemical synthesis of fluorine-18 and H-2 dual-labeled altanserin has been described.Other ligands for other parts of the serotonin system used in PET studies are, e.g., DASB, ketanserin, and WAY-100635.

Antitarget

In pharmacology, an antitarget (or off-target) is a receptor, enzyme, or other biological target that, when affected by a drug, causes undesirable side-effects. During drug design and development, it is important for pharmaceutical companies to ensure that new drugs do not show significant activity at any of a range of antitargets, most of which are discovered largely by chance.Among the best-known and most significant antitargets are the hERG channel and the 5-HT2B receptor, both of which causing long-term problems with heart function that can prove fatal (long QT syndrome and cardiac fibrosis, respectively), in a small but unpredictable proportion of users. Both of these targets were discovered as a result of high levels of distinctive side-effects during the marketing of certain medicines, and, while some older drugs with significant hERG activity are still used with caution, most drugs that have been found to be strong 5-HT2B agonists were withdrawn from the market, and any new compound will almost always be discontinued from further development if initial screening shows high affinity for these targets.Agonism of the 5-HT2A receptor is an antitarget due to the hallucinogenic effects that 5-HT2A receptor agonists are associated with. According to David E. Nichols, "Discussions over the years with many colleagues working in the pharmaceutical industry have informed me that if upon screening a potential new drug is found to have serotonin 5-HT2A agonist activity, it nearly always signals the end to any further development of that molecule." There are some exceptions however, for instance efavirenz and lorcaserin, which can activate the 5-HT2A receptor and cause psychedelic effects at high doses.

Glemanserin

Glemanserin (INN) (developmental code name MDL-11,939) is a drug which acts as a potent and selective 5-HT2A receptor antagonist. The first truly selective 5-HT2A ligand to be discovered, glemanserin resulted in the development of the widely used and even more potent and selective 5-HT2A receptor antagonist volinanserin (MDL-100,907), which is a fluorinated analogue. Though it was largely superseded in scientific research by volinanserin, glemanserin was investigated clinically for the treatment of generalized anxiety disorder. However, it was ultimately found to be ineffective and was not marketed.

Head-twitch response

The head-twitch response (HTR) is a rapid side-to-side head movement that occurs in mice and rats after the serotonin 5-HT2A receptor is activated. The prefrontal cortex may be the neuroanatomical locus mediating the HTR. Many serotonergic hallucinogens, including lysergic acid diethylamide (LSD), induce the head-twitch response, and so the HTR is used as a behavioral model of hallucinogen effects. However while there is generally a good correlation between compounds that induce head twitch in mice and compounds that are hallucinogenic in humans, it is unclear whether the head twitch response is primarily caused by 5-HT2A receptors, 5-HT2C receptors or both, but recent evidence shows that the HTR is mediated by the 5-HT2A receptor and modulated by the 5-HT2C receptor. Also, the effect can be non-specific, with head twitch responses also produced by some drugs that do not act through 5-HT2 receptors, such as phencyclidine, yohimbine, atropine and cannabinoid receptor antagonists. As well, compounds such as 5-HTP, fenfluramine and 1-Methylpsilocin can also produce head twitch and do stimulate serotonin receptors, but are not hallucinogenic in humans. This means that while the head twitch response can be a useful indicator as to whether a compound is likely to display hallucinogenic activity in humans, the induction of a head twitch response does not necessarily mean that a compound will be hallucinogenic, and caution should be exercised when interpreting such results.

List of investigational antipsychotics

This is a list of investigational antipsychotics, or antipsychotics that are currently under development for clinical use but are not yet approved. Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses.

Lubazodone

Lubazodone (developmental code names YM-992, YM-35995) is an experimental antidepressant which was under development by Yamanouchi for the treatment for major depressive disorder in the late 1990s and early 2000s but was never marketed. It acts as a serotonin reuptake inhibitor (Ki for SERT = 21 nM) and 5-HT2A receptor antagonist (Ki = 86 nM), and hence has the profile of a serotonin antagonist and reuptake inhibitor (SARI). The drug has good selectivity against a range of other monoamine receptors, with its next highest affinities being for the α1-adrenergic receptor (Ki = 200 nM) and the 5-HT2C receptor (Ki = 680 nM). Lubazodone is structurally related to trazodone and nefazodone, but is a stronger serotonin reuptake inhibitor and weaker as a 5-HT2A receptor antagonist in comparison to them and is more balanced in its actions as a SARI. It reached phase II clinical trials for depression, but development was discontinued in 2001 reportedly due to the "erosion of the SSRI market in the United States".

Rs6314

In genetics, rs6314, also called His452Tyr or H452Y, is a gene variation, a single nucleotide polymorphism (SNP), in the HTR2A gene that codes for the 5-HT2A receptor.

The SNP is located in exon 3 of the gene and the change between C and T results in a change between histidine (His) and tyrosine (Tyr) at the 452nd amino acid, i.e., it is a missense substitution.As 5-HT2A is a neuroreceptor the SNP has been investigated in connection with neuropsychiatric disorders

and other brain-related variables.

A 2003 study looked at memory performance and found that His/His subjects performed better.

Another study reported that the SNP had an effect on the memory performance in young adults.

This has been replicated by another group.The His452Tyr variant may influence cell signaling.rs6311, rs6313 and rs7997012 are other investigated SNPs in the HTR2A gene.

Serotonin receptor agonist

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

Setoperone

Setoperone is a compound that is a ligand to the 5-HT2A receptor.

It can be radiolabeled with the radioisotope fluorine-18 and used as a radioligand with positron emission tomography (PET).

Several research studies have used the radiolabeled setoperone in neuroimaging for the studying neuropsychiatric disorders, such as depression

or schizophrenia.

TCB-2

TCB-2 is a hallucinogen discovered in 2006 by Thomas McLean working in the lab of David Nichols at Purdue University where it was named 2C-BCB. It is a conformationally-restricted derivative of the phenethylamine 2C-B, also a hallucinogen, and acts as a potent agonist for the 5-HT2A and 5-HT2C receptors with a Ki of 0.26 nM at the human 5-HT2A receptor. In drug-substitution experiments in rats, TCB-2 was found to be of similar potency to both LSD and Br-DFLY, ranking it among the most potent phenethylamine hallucinogens yet discovered. This high potency and selectivity has made TCB-2 useful for distinguishing 5-HT2A mediated responses from those produced by other similar receptors. TCB-2 has similar but not identical effects in animals to related phenethylamine hallucinogens such as DOI, and has been used for studying how the function of the 5-HT2A receptor differs from that of other serotonin receptors in a number of animal models, such as studies of cocaine addiction and neuropathic pain.

UH-232

UH-232 ((+)-UH232) is a drug which acts as a subtype selective mixed agonist-antagonist for dopamine receptors, acting as a weak partial agonist at the D3 subtype, and an antagonist at D2Sh autoreceptors on dopaminergic nerve terminals. This causes dopamine release in the brain and has a stimulant effect, as well as blocking the behavioural effects of cocaine. It may also serve as a 5-HT2A receptor agonist, based on animal studies.

It was investigated in clinical trials for the treatment of schizophrenia, but unexpectedly caused symptoms to become worse.

Volinanserin

Volinanserin (INN) (developmental code name MDL-100,907) is a highly selective 5-HT2A receptor antagonist that is frequently used in scientific research to investigate the function of the 5-HT2A receptor. It was also tested in clinical trials as a potential antipsychotic, antidepressant, and treatment for insomnia but was never marketed.

Gene location (Human)
Chromosome 13 (human)
Chr.Chromosome 13 (human)[1]
Chromosome 13 (human)
Genomic location for HTR2A
Genomic location for HTR2A
Band13q14.2Start46,831,550 bp[1]
End46,897,076 bp[1]
Gene location (Mouse)
Chromosome 14 (mouse)
Chr.Chromosome 14 (mouse)[2]
Chromosome 14 (mouse)
Genomic location for HTR2A
Genomic location for HTR2A
Band14 D3|14 39.37 cMStart74,640,840 bp[2]
End74,709,494 bp[2]
RNA expression pattern
PBB GE HTR2A 211616 s at fs


PBB GE HTR2A 207135 at fs
More reference expression data
Gene ontology
Molecular function 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding
G-protein coupled receptor activity
virus receptor activity
signal transducer activity
drug binding
G-protein alpha-subunit binding
G-protein coupled serotonin receptor activity
serotonin binding
neurotransmitter receptor activity
protein binding
macromolecular complex binding
Cellular component cytoplasm
integral component of membrane
cytosol
cell projection
membrane
cell body fiber
integral component of plasma membrane
dendritic shaft
axon
neuronal cell body
caveola
cytoplasmic vesicle
plasma membrane
dendrite
glutamatergic synapse
integral component of postsynaptic membrane
integral component of presynaptic membrane
Biological process detection of mechanical stimulus involved in sensory perception of pain
release of sequestered calcium ion into cytosol
regulation of dopamine secretion
phospholipase C-activating serotonin receptor signaling pathway
urinary bladder smooth muscle contraction
positive regulation of MAP kinase activity
behavioral response to cocaine
positive regulation of cytosolic calcium ion concentration
positive regulation of kinase activity
positive regulation of phosphatidylinositol biosynthetic process
aging
cellular calcium ion homeostasis
cell death
memory
activation of phospholipase C activity
detection of temperature stimulus involved in sensory perception of pain
protein localization to cytoskeleton
sleep
positive regulation of vasoconstriction
positive regulation of cell proliferation
negative regulation of potassium ion transport
positive regulation of ERK1 and ERK2 cascade
artery smooth muscle contraction
positive regulation of peptidyl-tyrosine phosphorylation
Viral entry
phosphatidylinositol 3-kinase signaling
nociception
temperature homeostasis
viral process
positive regulation of fat cell differentiation
positive regulation of glycolytic process
negative regulation of synaptic transmission, glutamatergic
signal transduction
chemical synaptic transmission
response to drug
serotonin receptor signaling pathway
phospholipase C-activating G-protein coupled receptor signaling pathway
G-protein coupled receptor signaling pathway
animal behavior
regulation of synaptic vesicle exocytosis
G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
Sources:Amigo / QuickGO
History
Biology
Symptoms
Treatment
Organizations
Notable people
Popular culture
Related
Psychedelics
(5-HT2A
agonists)
Dissociatives
(NMDAR
antagonists)
Deliriants
(mAChR
antagonists)
Others
GABAA
GABAB
H1
α2-Adrenergic
5-HT2A
Melatonin
Orexin
α2δ VDCC
Others
5-HT1
5-HT2
5-HT37

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