# 5-HT2A receptor

The 5-HT$_{2A}$ receptor is a subtype of the 5-HT$_2$ receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT$_{2A}$ receptor is a cell surface receptor, but has several intracellular locations.
Like all 5-HT$_2$ receptors, the 5-HT$_{2A}$ receptor is G$_q$/G$_{11}$-protein coupled. This is the main excitatory receptor subtype among the GPCRs for serotonin. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially atypical antipsychotics.
Downregulation of post-synaptic 5-HT$_{2A}$ receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics. Suicidal and otherwise depressed patients have had more 5-HT$_{2A}$ receptors than normal patients. These findings suggest that post-synaptic 5-HT$_{2A}$ overdensity is involved in the pathogenesis of depression.
Paradoxical down-regulation of 5-HT$_{2A}$ receptors can be observed with several 5-HT$_{2A}$ antagonists. Thus, instead of tolerance, reverse-tolerance would be expected from 5-HT$_{2A}$ antagonists. However, there is at least one antagonist at this site which has been shown to up-regulate 5-HT$_{2A}$ receptors. Additionally, a couple of other antagonists may have no effect on 5-HT$_{2A}$ receptor number. Nevertheless, upregulation is the exception rather than the rule. Neither tolerance nor rebound is observed in humans with regard to the slow-wave sleep (SWS) promoting effects of 5-HT$_{2A}$ antagonists.

## Signaling cascade

The 5-HT$_{2A}$ receptor is known primarily to couple to the Gα$_q$ signal transduction pathway. Upon receptor stimulation with agonist, Gα$_q$ and β-γ subunits dissociate to initiate downstream effector pathways. Gα$_q$ 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 Ca$^{2+}$ release.

## History

5-HT receptors were split into two classes by John Gaddum and Picarelli when it was discovered that some of the serotonin-induced changes in the gut could be blocked by morphine, while the remainder of the response was inhibited by dibenzyline, leading to the naming of M and D receptors, respectively. 5-HT$_{2A}$ is thought to correspond to what was originally described as D subtype of 5-HT receptors by Gaddum and Picarelli. In the era before molecular cloning, when radioligand binding and displacement was the only major tool, spiperone and LSD were shown to label two different 5-HT receptors, and neither of them displaced morphine, leading to naming of the 5-HT$_1$, 5-HT$_2$ and 5-HT$_3$ receptors, corresponding to high affinity sites from LSD, spiperone and morphine, respectively. Later it was shown that the 5-HT$_2$ was very close to 5-HT$_{1C}$ and thus were grouped together, renaming the 5-HT$_2$ into 5-HT$_{2A}$. Thus, the 5-HT$_2$ receptor family is composed of three separate molecular entities: the 5-HT$_{2A}$ (formerly known as 5-HT$_2$ or D), the 5-HT$_{2B}$ (formerly known as 5-HT$_{2F}$) and the 5-HT$_{2C}$ (formerly known as 5-HT$_{1C}$) receptors.

## Distribution

5-HT$_{2A}$ is expressed widely throughout the central nervous system (CNS). It is expressed near most of the serotonergic 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 by enhancing glutamate release followed by a complex range of interactions with the 5-HT$_{1A}$, GABA$_A$, adenosine A$_1$, AMPA, mGluR$_{2/3}$, mGlu5, and OX$_2$ receptors. In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer, and in the Purkinje cells.
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-HT$_{2A}$ mRNA expression has been observed in human monocytes. Whole-body distribution of the 5-HT$_{2A/2C}$ receptor agonist, [11C]Cimbi-36 show uptake in several internal organs and brown adipose tissue (BAT), but it is not clear if this represents specific 5-HT$_{2A}$ receptor binding.

## Effects

Physiological processes mediated by the receptor include:
* CNS: neuronal excitation, hallucinations, out-of-body experiences, and fear. Primarily responsible for the psychedelic effects associated with 5-HT$_{2A}$ receptor agonists such as LSD, DMT, etc.
* Activation of the 5-HT$_{2A}$ receptor with 2,5-dimethoxy-4-iodoamphetamine (DOI) produces potent anti-inflammatory effects in several tissues including cardiovascular and gut. Other 5-HT$_{2A}$ agonists like LSD also have potent anti-inflammatory effects against TNF-alpha-induced inflammation.
* Activation of the 5-HT$_{2A}$ receptor in hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin.
* Role in memory and learning.
* Role in arthralgia.
* Role in Alzheimer's disease.
* Smooth muscle contraction in the gut.
* Probable role in sleep paralysis.
* Probable role in aging.

## Ligands
### Agonists

Activation of the 5-HT$_{2A}$ 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-HT$_{2A}$ 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. Agonists acting at 5-HT$_{2A}$ receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity. Some findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT$_{2A}$–mGlu2 and not by monomeric 5-HT$_{2A}$ receptors. However, newer research suggests that 5HT$_{2A}$ and mGlu2 receptors do not physically associate with each other, so the former findings have questionable relevance. Agonists enhance dopamine in PFC, enhance memory and play an active role in attention and learning.

#### Full agonists

* 25B-NBOMe – also known as Cimbi-36; used as a PET imaging tool for visualizing the 5-HT$_{2A}$ receptor
* 25I-NBOH and its 2-methoxy-analog 25I-NBOMe
* BMB-202 – highly selective
* $^{18}$F FECIMBI-36 – radiolabelled agonist ligand for mapping 5-HT$_{2A}$ / 5-HT$_{2C}$ receptor distribution
* 5-Methoxytryptamine – full agonist to several serotonin receptors.
* O-4310 – 5-HT$_{2A}$ selective, claimed to have 100× selectivity over 5-HT$_{2C}$ and be inactive at 5-HT$_{2B}$
* PHA-57378 – dual 5-HT$_{2A}$ / 5-HT$_{2C}$ agonist, anxiolytic effects in animal studies.
* TCB-2

#### Partial agonists

* 25C-NBOMe
* 25CN-NBOH – 100× selectivity for 5-HT$_{2A}$ over 5-HT$_{2C}$, 46× selectivity over 5-HT$_{2B}$.
* 3-Carboxy indole PB-22 (1-pentyl-indole-3-carboxylic acid) – a metabolite of the synthetic cannabinoid PB-22, partial agonist at 5-HT$_{2A}$
* BMB-201 – non-hallucinogenic-like in animals
* Bromo-DragonFLY
* DMBMPP – a structurally constrained derivative of 25B-NBOMe, which acts as a potent partial agonist with 124× selectivity for 5-HT$_{2A}$ over 5-HT$_{2C}$, making it the most selective agonist ligand identified to date.
* (R)-DOI – traditionally the most common 5-HT$_{2A}$ reference agonist used in research
* Efavirenz – an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT$_{2A}$.
* IHCH-7113 – 5-HT$_{2A}$ agonist derived by simplification of the 5-HT$_{2A}$ antagonist antipsychotic lumateperone.
* Lisuride – an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT$_{2A}$ / 5-HT$_{2C}$ agonist and 5-HT$_{2B}$ antagonist.
* Mefloquine – an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT$_{2A}$ and/or 5-HT$_{2C}$ receptors.
* Methysergide – a congener of methylergonovine, used in treatment of migraine blocks 5-HT$_{2A}$ and 5-HT$_{2C}$ receptors, but sometimes acts as partial agonist, in some preparations.
* Piperidine derivatives such as OSU-6162, which acts as a partial agonist at both 5-HT$_{2A}$ and dopamine D$_2$ receptors, and Z3517967757.
* Quipazine – 5-HT$_{2A}$ agonist but also potent 5-HT$_3$ agonist.
* SN-22 – partial agonist at all three 5-HT$_2$ subtypes
* Some benzazepines and similar compounds related to lorcaserin such as SCHEMBL5334361 are potent 5-HT$_{2A}$ agonists as well as showing action at 5-HT$_{2C}$.
* Substituted tetrahydro-β-carboline
* Tetrahydropyridine derivatives such as (R)-69, Z4154032166 and WXVL_BT0793LQ2118.
* Zalsupindole (DLX-001; AAZ-A-154) – non-hallucinogenic but retains antidepressant effects in animals.

#### Selective agonists

* 25CN-NBOH
* BMB-202
* DMBMPP
* LPH-5
* LPH-48
* Lysergine
* O-4310

#### Peripherally selective agonists

One effect of 5-HT$_{2A}$ receptor activation is a reduction in intraocular pressure, and so 5-HT$_{2A}$ 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. 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.

### Antagonists

* 2-Alkyl-4-aryl-tetrahydro-pyrimido-azepines – subtype selective antagonists (35 g: 60-fold).
* 5-MeO-NBpBrT
* AMDA and related derivatives – family of selective 5-HT$_{2A}$ antagonists.
* Atypical antipsychotics – e.g., quetiapine, and asenapine are relatively potent antagonists of 5-HT$_{2A}$
* Brexpiprazole – an atypical antipsychotic, is a potent antagonist at 5-HT$_{2A}$ receptors (K$_i$ = 0.47 nM in humans).
* Cariprazine
* Cyclobenzaprine – a strong antagonist of both 5-HT$_{2A}$ and 5-HT$_{2C}$ receptors
* Cyproheptadine
* Ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, but a few ergot derivatives such as metergoline and nicergoline bind preferentially to members of the 5-HT$_2$ receptor family.
* Hydroxyzine (Atarax) (minor effect)
* Ketanserin – The discovery of ketanserin was a landmark in the pharmacology of 5-HT$_2$ receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well-known antihypertensive action through 5-HT$_2$ receptor family, but through its high affinity for alpha$_1$ adrenergic receptors. It also has high affinity for H$_1$ histaminergic receptors equal to that at 5-HT$_{2A}$ receptors. Compounds chemically related to ketanserin such as ritanserin are more selective 5-HT$_{2A}$ receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT$_{2A}$ receptor antagonists, also potently inhibits 5-HT$_{2C}$ receptors.
* LY-367,265 – dual 5-HT$_{2A}$ antagonist / SSRI with antidepressant effects
* Nantenine
* Nefazodone – blocks post-synaptic 5-HT$_{2A}$ receptors, and to a lesser extent inhibits pre-synaptic serotonin and norepinephrine reuptake.
* Niaprazine
* Opipramol – atypical antidepressant
* Pizotifen – a non-selective antagonist.
* Trazodone – a potent 5-HT$_{2A}$ antagonist, as well as an antagonist on other serotonin receptors.
* Tetracyclic antidepressants – mianserin, mirtazapine, maprotiline
* Tricyclic antidepressants (TCAs) – e.g., amitriptyline, nortriptyline, amoxapine, clomipramine, doxepin, maprotiline, imipramine, iprindole
* Typical antipsychotics – e.g., haloperidol and chlorpromazine (minor)
* Volinanserin (MDL100907, M100907) – the most potent 5-HT$_{2A}$ antagonist; underwent a few clinical trials but was ultimately never marketed.

#### Peripherally selective antagonists

* BW-501C67
* Sarpogrelate
* Xylamidine

#### Antagonists and cardiovascular disease

Increased 5-HT$_{2A}$ expression is observed in patients with coronary thrombosis, and the receptor has been associated with processes that influence atherosclerosis. As the receptor is present in coronary arteries and capable of mediating vasoconstriction, 5-HT$_{2A}$ has also been linked to coronary artery spasms. 5-HT antagonism, therefore, has potential in the prevention of cardiovascular disease, however, no studies have been published so far.

### Inverse agonists

* AC-90179 – potent and selective inverse agonist at 5-HT$_{2A}$, also 5-HT$_{2C}$ antagonist.
* Atypical antipsychotics – clozapine, iloperidone, olanzapine, paliperidone, risperidone
* Eplivanserin (Sanofi Aventis) – sleeping pill that reached phase II trials (but for which the application for approval was withdrawn), acts as a selective 5-HT$_{2A}$ inverse agonist.
* Nelotanserin (APD-125) – selective 5-HT$_{2A}$ inverse agonist developed by Arena Pharmaceuticals for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials.
* 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.

### Positive allosteric modulators

Positive allosteric modulators of the serotonin 5-HT$_{2A}$ receptor have been identified. These include CTW0404 and CTW0419. They selectively potentiated the serotonin 5-HT$_{2A}$ receptor without affecting the serotonin 5-HT$_{2B}$ and 5-HT$_{2C}$ receptors. Unlike serotonin 5-HT$_{2A}$ receptor agonists, they did not substitute for the serotonergic psychedelic (R)-DOI in drug discrimination tests and did not produce the head-twitch response, suggesting that they lack hallucinogenic effects. Instead, they blunted the (R)-DOI-induced head-twitch response.

### Functional selectivity

5-HT$_{2A}$-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.
Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT$_{2A}$ 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-HT$_{2A}$ agonists. One known example of differences in signal transduction is between the two 5-HT$_{2A}$ agonists serotonin and DOI that involves differential recruitment of intracellular proteins called β-arrestins, more specifically arrestin beta 2. Cyclopropylmethanamine derivatives such as (−)-19 have also been shown to act as 5-HT$_{2A/2C}$ agonists with functional selectivity for Gq-mediated signaling compared with β-arrestin recruitment.

## Genetics

The 5-HT$_{2A}$ 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.
Probable role in fibromyalgia as the T102C polymorphisms of the gene 5HT2A were common in fibromyalgia patients.
Human HTR2A gene is thought to consist of 3 introns and 4 exons and to overlap with human gene HTR2A-AS1 which consists of 18 exons. There are over 200 organisms that have orthologs with the human HTR2A. Currently, the best documented orthologs for HTR2A gene are the mouse, and zebrafish. There are 8 paralogs for the HTR2A gene. The HTR2A gene is known to interact and activate G-protein genes such as GNA14, GNAI1, GNAI3, GNAQ, and GNAZ. These interactions are critical for cell signaling and homeostasis in many organisms.
In human brain tissue, regulation of HTR2A varies depending on the region: frontal cortex, amygdala, thalamus, brain stem and cerebellum. In a paper from 2016, they found that HTR2A undergoes a variety of different splicing events, including utilization of alternative splice acceptor sites, exon skipping, rare exon usage, and intron retention.

### Mechanisms of regulation

There are a few mechanisms of regulation for HTR2A gene such regulated by DNA methylation at particular transcript binding sites. Another mechanism for the correct regulation of gene expression is achieved through alternative splicing. This is a co-transcriptional process, which allows the generation of multiple forms of mRNA transcript from a single coding unit and is emerging as an important control point for gene expression. In this process, exons or introns can be either included or excluded from precursor-mRNA resulting in multiple mature mRNA variants. These mRNA variants result in different isoforms which may have antagonistic functions or differential expression patterns, yielding plasticity and adaptability to the cells. One study found that the common genetic variant rs6311 regulates expression of HTR2A transcripts containing the extended 5' UTR.

### Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as major depressive disorder. and a strong link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia.
This polymorphism has also been studied in relation to suicide attempts, with a study finding excess of the G/G and G/A genotypes among the suicide attempters. A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.
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.
Polymorphisms in the promoter gene coding Early growth response 3 (EGR3) are associated with schizophrenia. Studies have demonstrated a relationship between EGR3 and HTR2A, and schizophrenia-like behaviors in transgenic animals. Exactly how these results translate over to further biopsychological understanding of schizophrenia is still widely debated. There is some evidence that dysfunction of HTR2A can impact pharmacological interventions.
Several studies have assessed a relationship between 5-hydroxytryptamine (serotonin) 2A receptor (5-HTR2A) gene polymorphisms with an increased risk of suicidal behavior. One study revealed that T102C polymorphism is associated with suicidal behavior but other studies failed to replicate these findings and found no association between polymorphism and suicidal behavior.

#### Treatment response

Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.

#### Associations with substance abuse

Polymorphisms in the 5-HT$_{2A}$ receptor coding gene HTR2A (rs6313 and s6311) have been shown to have conflicting associations with alcohol misuse. For example, A polymorphism in the 5-HT$_{2A}$ receptor coding gene HTR2A (rs6313) was reported to predict lower positive alcohol expectancy, higher refusal self-efficacy, and lower alcohol misuse in a sample of 120 young adults. However, this polymorphism did not moderate the linkages between impulsivity, cognition, and alcohol misuse. There are conflicting results as other studies have found associations between T102C polymorphisms alcohol misuse.

#### Drug impact on gene expression

There is some evidence that methylation patterns may contribute to relapse behaviors in people who use stimulants. In mice, psychotropic drugs such as DOI, LSD, DOM, and DOB which produced differing transcriptional patterns among several different brain regions.

## Methods to analyse the receptor

The receptor can be analysed by neuroimaging, radioligand, genetic analysis, measurements of ion flows, and other ways.

### Neuroimaging

The 5-HT$_{2A}$ receptors may be imaged with PET-scanners using the fluorine-18-altanserin, MDL 100,907 or [$^{11}$C]Cimbi-36 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.
Altanserin uptake decreases with age reflecting a loss of specific 5-HT$_{2A}$ receptors with age.

### Other

Western blot with an affinity-purified antibody and examination of 5-HT$_{2A}$ receptor protein samples by electrophoresis has been described. Immunohistochemical staining of 5-HT$_{2A}$ receptors is also possible.