5-HT_2A receptor

The 5-HT_2A receptor is a subtype of the

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.^[9]

Paradoxical down-regulation of 5-HT_2A receptors can be observed with several 5-HT_2A antagonists.^[10] 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.^[10][11] Additionally, a couple of other antagonists may have no effect on 5-HT_2A receptor number.^[12] 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.^[13]

Signaling cascade

The 5-HT_2A receptor is known primarily to couple to the

5-HT_2A is expressed widely throughout the central nervous system (CNS).^[18] It is expressed near most of the serotonergic terminal rich areas, including

• 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.^[35][36]
• Activation of the 5-HT_2A receptor with
  TNF-alpha-induced inflammation.^[37][38]
• Activation of the 5-HT_2A receptor in hypothalamus causes increases in hormonal levels of
  ACTH, corticosterone, and renin.^[39][40]
• Role in memory and learning[21]^[41][42]
• Role in arthralgia.^[43][44]
• Role in Alzheimer's disease.^[45]
• Smooth muscle contraction in the gut.^[5]
• Probable role in sleep paralysis.^[36]
• Probable role in
  aging.^[46][47]

Activation of the 5-HT_2A

• 25I-NBOH and its 2-methoxy-analog 25I-NBOMe^[55]
• radiolabelled agonist ligand for mapping 5-HT_2A / 5-HT_2C receptor distribution^[56]
• TCB-2^[57]
• Mexamine
   – 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.^[58]
• 25B-NBOMe – also known as Cimbi-36; used as a PET imaging tool for visualizing the 5-HT_2A receptor^[59]

Partial agonists

• 25C-NBOMe
• 25CN-NBOH – 100× selectivity for 5-HT_2A over 5-HT_2C, 46× selectivity over 5-HT_2B.^[60]
• AAZ-A-154 – non-hallucinogenic but retains antidepressant effects in animals.^[61]
• Bromo-DragonFLY^[62]
• (R)-DOI – traditionally the most common 5-HT_2A reference agonist used in research^[63]
• Efavirenz – an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT_2A.^[64]
• 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.^[65]
• Lisuride – an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT_2A / 5-HT_2C agonist^[66] and 5-HT_2B antagonist.^[67]
• Mefloquine – an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT_2A and/or 5-HT_2C receptors.^[68]
• methylergonovine, used in treatment of migraine
  blocks 5-HT_2A and 5-HT_2C receptors, but sometimes acts as partial agonist, in some preparations.
• dopamine D₂ receptors, and Z3517967757
  .
• Quipazine – 5-HT_2A agonist but also potent 5-HT₃ agonist.^[69]
• SN-22 – partial agonist at all three 5-HT₂ subtypes
• 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^[70]
• 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.^{[71][72][73][74][75]}
• IHCH-7113 – 5-HT_2A agonist derived by simplification of the 5-HT_2A antagonist antipsychotic lumateperone.^[76]
• Tetrahydropyridine derivatives such as (R)-69,^[77] Z4154032166 and WXVL_BT0793LQ2118.^[78]
• Substituted tetrahydro-β-carbolines ^[79]

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.^[80] 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.^[81]

Antagonists

• Volinanserin (MDL100907, M100907) – the most potent 5-HT_2A antagonist.^[82] It underwent a few clinical trials but never got marketed.
• Trazodone – a potent 5-HT_2A antagonist, as well as an antagonist on other serotonin receptors.
• Cyclobenzaprine – a strong antagonist of both 5-HT_2A and 5-HT_2C receptors
• Brexpiprazole – an atypical antipsychotic, is a potent antagonist at 5-HT_2A receptors (K_i = 0.47 nM in humans).^[83][84]
• Most tricyclic antidepressants (TCAs) – e.g., amitriptyline, nortriptyline, amoxapine, clomipramine, doxepin, maprotiline, imipramine, iprindole^[85]
• Tetracyclic antidepressants – mianserin,^[85] mirtazapine, maprotiline
• Nefazodone – blocks post-synaptic 5-HT_2A receptors, and to a lesser extent inhibits pre-synaptic serotonin and norepinephrine reuptake.
• Atypical antipsychotics – e.g., clozapine, olanzapine, quetiapine, risperidone and asenapine are relatively potent antagonists of 5-HT_2A as are some of the lower potency old generation/typical antipsychotics.
• Cyproheptadine
• Pizotifen – a non-selective antagonist.^[86]
• LY-367,265 – dual 5-HT_2A antagonist / SSRI with antidepressant effects
• 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines – subtype selective antagonists (35 g: 60-fold).^[87]
• AMDA and related derivatives – family of selective 5-HT_2A antagonists.^{[88][89][90][91][92]}
• Typical antipsychotics – e.g., haloperidol and chlorpromazine
  (minor)
• Opipramol – atypical antidepressant
• Hydroxyzine (Atarax) (minor effect)
• 5-MeO-NBpBrT
• Niaprazine
• Cariprazine
• Nantenine
• Although ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, a few ergot derivatives such as metergoline and nicergoline 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-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.

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.^[93] As the receptor is present in coronary arteries^[94] and capable of mediating vasoconstriction, 5-HT_2A has also been linked to coronary artery spasms.^[95] 5-HT antagonism, therefore, has potential in the prevention of cardiovascular disease, however, no studies have been published so far.^[93]

Inverse agonists

• AC-90179 – potent and selective inverse agonist at 5-HT_2A, also 5-HT_2C antagonist.^[96][97]
• 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.^[98]
• 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.
• 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.^{[99][100][101][102][103]}

Functional selectivity

5-HT_2A-receptor

Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT_2A agonists that produce

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

Probable role in fibromyalgia as the T102C polymorphisms of the gene 5HT2A were common in fibromyalgia patients.^[111]

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.^[112] There are over 200 organisms that have orthologs with the human HTR2A. Currently, the best documented orthologs for HTR2A gene are the mouse,^[113] and zebrafish.^[114] 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.^[115] These interactions are critical for cell signaling^[116][117] and homeostasis ^[118] in many organisms.^[119]

In human brain tissue, regulation of HTR2A varies depending on the region:^[112] 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.^[112]

Mechanisms of regulation

There are a few mechanisms of regulation for HTR2A gene such regulated by DNA methylation at particular transcript binding sites.^[120][121] 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.^[122] These mRNA variants result in different isoforms which may have antagonistic functions or differential expression patterns, yielding plasticity and adaptability to the cells.^[123] One study found that the common genetic variant rs6311 regulates expression of HTR2A transcripts containing the extended 5' UTR.^[112]

Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and

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.^[129]

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.^[130][131] Exactly how these results translate over to further biopsychological understanding of schizophrenia is still widely debated.^[132][133] There is some evidence that dysfunction of HTR2A can impact pharmacological interventions.^[134]

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 ^[135] but other studies failed to replicate these findings and found no association between polymorphism and suicidal behavior.^[136]

Treatment response

Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.^[137]

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.^[138] There are conflicting results as other studies have found associations between T102C polymorphisms alcohol misuse.^[139][140]

Drug impact on gene expression

There is some evidence that methylation patterns may contribute to

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

Neuroimaging

The 5-HT_2A receptors may be imaged with

Altanserin uptake decreases with

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.[5]

References