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The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and functions as a G protein-coupled receptor (GPCR). It is a cell surface receptor that activates multiple intracellular signalling cascades. Like all 5-HT2 receptors, the 5-HT2A receptor is coupled to the Gq/G11 signaling pathway. It is the primary excitatory receptor subtype among the serotonin-responsive GPCRs. The 5-HT2A receptor was initially noted for its central role as the primary target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. It later regained research prominence when found to mediate, at least in part, the effects of many antipsychotic drugs, particularly atypical antipsychotics. Downregulation of post-synaptic 5-HT2A receptors is an adaptive response triggered by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics. Elevated 5-HT2A receptor density has been observed in suicidal and otherwise depressed patients, suggesting that post-synaptic 5-HT2A receptor overexpression may contribute to the pathogenesis of depression. Paradoxically, several 5-HT2A receptor antagonists can also induce receptor downregulation. This effect may lead to reverse tolerance, rather than the expected development of tolerance. However, at least one antagonist has been shown to upregulate 5-HT2A receptor expression, and a few others appear to have no effect on receptor levels. Nonetheless, such upregulation remains the exception rather than the rule. Importantly, neither tolerance nor rebound has been observed in humans in relation to the slow-wave sleep (SWS)-promoting effects of 5-HT2A antagonists.


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 Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
, while 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. In the era before
molecular cloning Molecular cloning is a set of experimental methods in molecular biology that are used to assemble recombinant DNA molecules and to direct their DNA replication, replication within Host (biology), host organisms. The use of the word ''cloning'' re ...
, 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-HT1, 5-HT2 and 5-HT3 receptors, corresponding to high affinity sites from LSD, spiperone and morphine, respectively. Later it was shown that the 5-HT2 was very close to 5-HT1C and thus were grouped 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.


Gene

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. 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
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...
s and 4
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
s 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 The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...
, brain stem and
cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...
. 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 In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation. Mechanis ...
, rare exon usage, and intron retention.


Transcriptional 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 Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
. 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.


Tissue distribution

5-HT2A is expressed widely throughout the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS). It is expressed near most of the serotonergic terminal rich areas, including
neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...
(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 Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
release followed by a complex range of interactions with the 5-HT1A, GABAA, adenosine A1, AMPA, mGluR2/3, mGlu5, and OX2 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 In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT2A mRNA expression has been observed in human monocytes. Whole-body distribution of the 5-HT2A/2C receptor agonist, 1Cimbi-36 show uptake in several internal organs and brown adipose tissue (BAT), but it is not clear if this represents specific 5-HT2A receptor binding.


Structure

The 5-HT2A receptor is a member of the class A (rhodopsin-like) G protein-coupled receptor (GPCR) family, characterized by seven transmembrane α-helices connected by extracellular and intracellular loops. Its ligand-binding pocket is composed of two adjacent subpockets: the orthosteric binding pocket (OBP) and an extended binding pocket (EBP), with a unique side-extended cavity near the orthosteric site that distinguishes it from related receptors. Ligands are anchored primarily through a conserved aspartate residue (D155^3.32) that interacts with their charged amine groups, while additional interactions involve hydrophobic contacts and hydrogen bonds with residues in both the OBP and EBP. Structural studies reveal that the receptor undergoes significant conformational changes upon activation, particularly in transmembrane helices 3 and 6, which facilitate G protein coupling and signal transduction. The extracellular ligand-binding pocket is closed by a flexible “lid,” and the intracellular region includes a short helix (H8) stabilized by π-stacking interactions, both of which contribute to the receptor's dynamic conformational landscape. These structural features underlie the receptor’s ability to recognize diverse ligands and mediate complex signaling behaviors. The cryo-EM
structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
s of the serotonin 5-HT2A receptor with a variety of serotonin 5-HT2A receptor agonists, including the tryptamines serotonin (
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
and endogenous
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
), psilocin ( psychedelic), and dimethyltryptamine (DMT) (psychedelic), the lysergamides LSD (psychedelic) and 2-bromo-LSD (BOL-148) (non-hallucinogenic), and the phenethylamines
mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...
(psychedelic) and RS130-180 ( β-arrestin- biased agonist with unknown hallucinogenic potential), have been solved and published by Bryan Roth and colleagues.


Function

The 5-HT2A receptor is a subtype of serotonin receptor that plays a critical role in the central nervous system, particularly in regions involved in cognition, learning, and memory. It is highly expressed in the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
, especially in layer V pyramidal neurons and certain
interneuron Interneurons (also called internuncial neurons, association neurons, connector neurons, or intermediate neurons) are neurons that are not specifically motor neurons or sensory neurons. Interneurons are the central nodes of neural circuits, enab ...
s, where it modulates thalamocortical information processing and may influence gamma oscillations, which are important for sensory integration and perception. Functionally, the 5-HT2A receptor is a G protein-coupled receptor (GPCR) that primarily signals through the phospholipase C (PLC) pathway, leading to the production of inositol triphosphate (IP3) and diacylglycerol, but it can also activate other signaling cascades such as arachidonic acid and 2-arachidonylglycerol pathways. Notably, the receptor exhibits "functional selectivity," meaning different ligands can differentially activate these signaling pathways, which is relevant for the distinct effects of hallucinogens, antipsychotics, and antidepressants that target the receptor. Activation of the 5-HT2A receptor by agonists is associated with enhanced cognition and hallucinogenic effects, while antagonists have antipsychotic and antidepressant properties. Dysregulation of 5-HT2A receptor function has been implicated in psychiatric disorders such as depression, schizophrenia, and drug addiction. Additionally, the receptor undergoes unique regulatory processes, including desensitization and internalization that are partly independent of β-arrestin, further distinguishing it from other GPCRs and influencing its response to long-term pharmacological modulation.


Signaling cascade

The 5-HT2A receptor is known primarily to couple to the q 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.


Effects

Physiological processes mediated by the receptor include: * CNS: neuronal excitation, hallucinations,
out-of-body experience An out-of-body experience (OBE or sometimes OOBE) is a phenomenon in which a person perceives the world as if from a location outside their physical body. An OBE is a form of autoscopy (literally "seeing self"), although this term is more common ...
s, and fear. Primarily responsible for the psychedelic effects associated with 5-HT2A receptor agonists such as LSD, DMT, etc. * Activation of the 5-HT2A receptor with 2,5-dimethoxy-4-iodoamphetamine (DOI) produces potent anti-inflammatory effects in several tissues including cardiovascular and gut. Other 5-HT2A agonists like LSD also have potent anti-inflammatory effects against TNF-alpha-induced
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
. * Activation of the 5-HT2A receptor in hypothalamus causes increases in hormonal levels of
oxytocin Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include Human bonding, ...
, prolactin, ACTH, corticosterone, and renin. * Role in memory and learning. * Role in arthralgia. * Role in
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. * Smooth muscle contraction in the gut. * Probable role in sleep paralysis. * Probable role in aging.


Ligands


Agonists

Activation of the 5-HT2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and
mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...
, 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. Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the
prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
are believed to mediate hallucinogenic activity. Some findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT2AmGlu2 and not by
monomer A monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or two- or three-dimensional network in a process called polymerization. Classification Chemis ...
ic 5-HT2A receptors. However, newer research suggests that 5HT2A 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. Serotonin 5-HT2A receptor agonists include serotonergic psychedelics and non-hallucinogenic agents. Psychedelics have widely been encountered as recreational drug or drugs of misuse, with potential clinical consequences such as
overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.
, hospitalization,
bad trip A bad trip (also known as challenging experiences, acute intoxication from hallucinogens, psychedelic crisis, or emergence phenomenon) is an acute adverse psychological reaction to the effects of Psychoactive drug, psychoactive substances, namely ...
s and worsened mental health, and rare
adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...
s such as seizures,
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
, and hallucinogen persisting perception disorder (HPPD). On the other hand, psychedelics and non-hallucinogenic serotonin 5-HT2A receptor agonists are under development as novel treatments for psychiatric disorders like depression,
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
, and
addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
as well as other conditions like cluster headaches. Both psychedelics and non-hallucinogenic serotonin 5-HT2A receptor agonists are claimed to act as psychoplastogens and this might be involved in their therapeutic effects.


Anti-inflammatory effects

Various serotonergic psychedelics, acting as serotonin 5-HT2A receptor agonists, have been found to be highly potent and efficacious anti-inflammatory and immunomodulatory agents in preclinical research (i.e.,
animal Animals are multicellular, eukaryotic organisms in the Biology, biological Kingdom (biology), kingdom Animalia (). With few exceptions, animals heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, ...
and '' in-vitro'' studies). In contrast to
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
s however, psychedelics with anti-inflammatory effects do not appear to suppress the immune system. Some psychedelics have been found to be far more potent in their anti-inflammatory effects than in their psychedelic effects. For instance, (''R'')-DOI is 30- to >50-fold more potent in producing anti-inflammatory effects than in producing psychedelic-like behavioral effects in animal research. Psilocin, the active form of psilocybin, has similar anti-inflammatory potency as (''R'')-DOI. The potencies of psychedelics and other serotonin 5-HT2A receptor agonists as anti-inflammatory drugs vary, with 2C-I, DOIB, 2C-B, 4-HO-DiPT, DOI, 2,5-DMA, DOET, DOM, psilocin, and 2C-H being highly potent and fully efficacious anti-inflammatories; TMA-2, 2C-B-Fly, TCB-2, ETH-LAD, LSD, and 2C-T-33 being partially efficacious anti-inflammatories; and lisuride, 1-methylpsilocin, 5-MeO-DMT, and DMT having negligible efficacy. Both non-hallucinogenic agents with full anti-inflammatory effects, such as 2,5-DMA, and non-anti-inflammatory agents with full psychedelic effects, such as DOTFM, are known. Hence, the psychedelic and anti-inflammatory effects of serotonin 5-HT2A receptor agonists appear to be fully dissociable. These effects appear to be mediated by different intracellular signaling pathways, although the exact pathways are unclear. Serotonin 5-HT2A receptor agonists with anti-inflammatory effects but reduced psychedelic effects, such as 2C-iBu (ELE-02), are under development for the potential treatment of inflammatory conditions. They may also have applications in the treatment of neuroinflammation. The anti-inflammatory effects of psychedelics might be involved in the claimed effects of psychedelic microdosing. Relatedly, LSD microdosing is being studied in the treatment of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
specifically for its anti-inflammatory effects.


Full agonists

* 25B-NBOMe also known as Cimbi-36; used as a PET imaging tool for visualizing the 5-HT2A receptor * 25I-NBOH and its 2-methoxy-analog 25I-NBOMe * BMB-202 highly selective * 18F FECIMBI-36 radiolabelled agonist ligand for mapping 5-HT2A / 5-HT2C receptor distribution * 5-Methoxytryptamine full agonist to several serotonin receptors. * O-4310 5-HT2A selective, claimed to have 100× selectivity over 5-HT2C and be inactive at 5-HT2B * PHA-57378 dual 5-HT2A / 5-HT2C agonist, anxiolytic effects in animal studies. * TCB-2


Partial agonists

* 25C-NBOMe *
25CN-NBOH 25CN-NBOH, also known as NBOH-2C-CN, is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. It is a member of the NBOMe family of psychedelic drug, psychedel ...
100× selectivity for 5-HT2A over 5-HT2C, 46× selectivity over 5-HT2B. * 3-Carboxy indole PB-22 (1-pentyl-indole-3-carboxylic acid) a metabolite of the synthetic cannabinoid PB-22, partial agonist at 5-HT2A * 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-HT2A over 5-HT2C, making it the most selective agonist ligand identified to date. * (''R'')-DOI traditionally the most common 5-HT2A reference agonist used in research * Efavirenz an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT2A. * IHCH-7113 5-HT2A agonist derived by simplification of the 5-HT2A antagonist antipsychotic lumateperone. * Lisuride an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT2A / 5-HT2C agonist and 5-HT2B antagonist. * Mefloquine an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT2A and/or 5-HT2C receptors. * 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. * Piperidine derivatives such as OSU-6162, which acts as a partial agonist at both 5-HT2A and dopamine D2 receptors, and Z3517967757. * Quipazine 5-HT2A agonist but also potent 5-HT3 agonist. * SN-22 partial agonist at all three 5-HT2 subtypes * Some benzazepines and similar compounds related to lorcaserin such as SCHEMBL5334361 are potent 5-HT2A agonists as well as showing action at 5-HT2C. * 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 25CN-NBOH, also known as NBOH-2C-CN, is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. It is a member of the NBOMe family of psychedelic drug, psychedel ...
* BMB-202 * DMBMPP * LPH-5 * LPH-48 * Lysergine * O-4310


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. 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

Serotonin 5-HT2A receptor antagonists, including many atypical antipsychotics, more selective agents like pimavanserin, and certain
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
s and hypnotics like trazodone,
mirtazapine Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, atypical tetracyclic antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks but ca ...
, tricyclic antidepressants, and hydroxyzine, are used in the treatment of psychiatric disorders and other conditions such as depression,
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
,
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
, and
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
. Ketanserin, a dual serotonin 5-HT2A receptor antagonist and α1-adrenergic receptor antagonist, is used as an antihypertensive agent. The non-selective serotonin 5-HT2A receptor antagonist cyproheptadine is frequently used
off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...
to treat
serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...
, albeit based on limited clinical evidence. Serotonin 5-HT2A receptor antagonists like ketanserin have been used as psychedelic antidotes or "trip killers" to manage the hallucinogenic effects of serotonergic psychedelics.


List of 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-HT2A antagonists. * Atypical antipsychotics e.g., quetiapine, and asenapine are relatively potent antagonists of 5-HT2A * Brexpiprazole an atypical antipsychotic, is a potent antagonist at 5-HT2A receptors (Ki = 0.47 nM in humans). * Cariprazine * Cyclobenzaprine a strong antagonist of both 5-HT2A and 5-HT2C 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-HT2 receptor family. * Hydroxyzine (Atarax) (minor effect) * Ketanserin – 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. * LY-367,265 dual 5-HT2A antagonist / SSRI with antidepressant effects * Nantenine * Nefazodone blocks post-synaptic 5-HT2A receptors, and to a lesser extent inhibits pre-synaptic serotonin and norepinephrine reuptake. * Niaprazine * Opipramol atypical antidepressant * Pizotifen a non-selective antagonist. Page 187 * Trazodone a potent 5-HT2A antagonist, as well as an antagonist on other serotonin receptors. *
Tetracyclic antidepressant Tetracyclic antidepressants (TeCAs) are a class of antidepressants that were first introduced in the 1970s. They are named after their tetracyclic chemical structure, containing four cyclic compound, rings of atoms, and are closely related to th ...
s mianserin,
mirtazapine Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, atypical tetracyclic antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks but ca ...
, 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-HT2A antagonist; underwent a few clinical trials but was ultimately never marketed.


Peripherally selective antagonists

* BW-501C67 * Sarpogrelate * Xylamidine


Antagonists and cardiovascular disease

Increased 5-HT2A expression is observed in patients with coronary thrombosis, and the receptor has been associated with processes that influence
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
. As the receptor is present in
coronary arteries The coronary arteries are the arteries, arterial blood vessels of coronary circulation, which transport oxygenated blood to the Cardiac muscle, heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any ...
and capable of mediating vasoconstriction, 5-HT2A 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-HT2A, also 5-HT2C 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-HT2A inverse agonist. * 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. * 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-HT2A receptor have been identified. These include CTW0404 and CTW0419. They selectively potentiated the serotonin 5-HT2A receptor without affecting the serotonin 5-HT2B and 5-HT2C receptors. Unlike serotonin 5-HT2A 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. The (''R'')-
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
of glaucine has also been reported to be a serotonin 5-HT2A receptor positive allosteric modulator. A dual serotonin 5-HT2C and 5-HT2A receptor positive allosteric modulator is the oleamide analogue JPC0323.


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. Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT2A agonists that produce headshakes in the
mouse A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...
and those that do not, such as lisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT2A agonists. 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. Cyclopropylmethanamine derivatives such as (−)-19 have also been shown to act as 5-HT2A/2C agonists with functional selectivity for Gq-mediated signaling compared with β-arrestin recruitment.


Serotonin-elevating drugs

Besides direct serotonin 5-HT2A receptor agonists, many drugs elevate serotonin levels and indirectly activate serotonin 5-HT2A receptors. Examples include
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
s and anxiolytics such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and serotonin precursors like tryptophan and 5-hydroxytryptophan (5-HTP). In addition, serotonin releasing agents (SRAs), including appetite suppressants like fenfluramine and chlorphentermine and entactogens like MDMA, elevate serotonin levels and indirectly activate serotonin 5-HT2A receptors similarly. Serotonin 5-HT2A receptor activation may be involved in the therapeutic effects of serotonin-elevating medications and appears to be importantly involved in the subjective effects of SRAs like MDMA. Serotonin-elevating drugs can cause
serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...
under certain circumstances, for instance in overdose or with combination of multiple serotonergic drugs, and the serotonin 5-HT2A receptor appears to be a key serotonin receptor in mediating this syndrome.


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-HT2A receptors may be imaged with PET-scanners using the fluorine-18- altanserin, MDL 100,907 or sup>11Cimbi-36 radioligands that binds to the neuroreceptor, e.g., one study reported a ''reduced'' binding of altanserin particularly in the
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
in patients with
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...
. Altanserin uptake decreases with age reflecting a loss of specific 5-HT2A receptors with age.


Other

Western blot with an affinity-purified antibody and examination of 5-HT2A receptor protein samples by electrophoresis has been described. Immunohistochemical staining of 5-HT2A receptors is also possible.


Clinical significance


Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...
. and a strong link with an
odds ratio An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of event A taking place in the presence of B, and the odds of A in the absence of B ...
of 1.3 has been found between the T102C polymorphism and
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
. The T102C polymorphism has also been studied in relation to suicide attempts, with a study finding excess of the C/C genotype among the suicide attempters. A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.Gene Overview of All Published Schizophrenia-Association Studies for HTR2A
SzGene database at Schizophrenia Research Forum.
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 Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
. 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-HT2A receptor coding gene ''HTR2A'' (rs6313 and s6311) have been shown to have conflicting associations with alcohol misuse. For example, A polymorphism in the 5-HT2A receptor coding gene ''HTR2A'' (rs6313) was reported to predict lower positive
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
expectancy, higher refusal
self-efficacy In psychology, self-efficacy is an individual's belief in their capacity to act in the ways necessary to reach specific goals. The concept was originally proposed by the psychologist Albert Bandura in 1977. Self-efficacy affects every area of hum ...
, 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.


See also

* Ultra-large-scale docking


References


Further reading

*


External links

* * * * {{Psychedelics Biology of attention deficit hyperactivity disorder Biology of bipolar disorder Serotonin receptors