5-HT2A receptor

Short description: Subtype of serotonin receptor

Generic protein structure example

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).[1] It is a cell surface receptor[2] that activates multiple intracellular signalling cascades.[3] 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.

## Contents

* 1 History
* 2 Gene
* 2.1 Transcriptional regulation
* 3 Tissue distribution
* 4 Structure
* 5 Function
* 5.1 Signaling cascade
* 5.2 Effects
* 6 Ligands
* 6.1 Agonists
* 6.1.1 Anti-inflammatory effects
* 6.1.2 Full agonists
* 6.1.3 Partial agonists
* 6.1.4 Selective agonists
* 6.1.5 Peripherally selective agonists
* 6.2 Antagonists
* 6.2.1 List of antagonists
* 6.2.2 Peripherally selective antagonists
* 6.2.3 Antagonists and cardiovascular disease
* 6.3 Inverse agonists
* 6.4 Positive allosteric modulators
* 6.5 Functional selectivity
* 6.6 Serotonin-elevating drugs
* 7 Methods to analyse the receptor
* 7.1 Neuroimaging
* 7.2 Other
* 8 Clinical significance
* 8.1 Associations with psychiatric disorders
* 8.1.1 Treatment response
* 8.1.2 Associations with substance abuse
* 8.1.3 Drug impact on gene expression
* 9 See also
* 10 References
* 11 Further reading
* 12 External links

## History

The serotonin receptors were split into two classes by John Gaddum and Picarelli in 1957 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 (phenoxybenzamine), leading to the naming of M and D receptors, respectively.[4][5] The 5-HT2A receptor is thought to correspond to what was originally described as D subtype of serotonin receptors by Gaddum and Picarelli.[4][5]

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-HT1, 5-HT2 and 5-HT3 receptors, corresponding to high affinity sites from LSD, spiperone and morphine, respectively.[6] Later, it was shown that the 5-HT2 receptor was very close to the 5-HT1C receptor and they were thus were grouped together, renaming the 5-HT2 receptor into 5-HT2A receptor and the 5-HT1C reeptor into the 5-HT2C receptor. 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.[7]

The serotonin 5-HT2A receptor was identified via radioligand binding in 1978 by Leysen and colleagues.[8][9] Peroutka and Snyder identified two distinct serotonin receptors and named them the 5-HT1 receptor and 5-HT2 receptor in 1979.[10][11] Later, both of these receptors were found to have several subtypes, including the serotonin 5-HT2A receptor.[10] The serotonin 5-HT2A receptor was characterized as a membrane protein by Wouters and colleagues in 1985.[8][12] The gene encoding the rat serotonin 5-HT2A receptor, HTR2A, was cloned in 1988 by Pritchett and colleagues.[8][13] The human gene was cloned by Branchek and colleagues in 1990.[10][14]

## Gene

Chromosome 13.

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.[15][16]

Probable role in fibromyalgia as the T102C polymorphisms of the gene 5HT2A were common in fibromyalgia patients.[17]

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.[18] There are over 200 organisms that have orthologs with the human HTR2A. Currently, the best documented orthologs for HTR2A gene are the mouse,[19] and zebrafish.[20] 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.[21] These interactions are critical for cell signaling[22][23] and homeostasis[24] in many organisms.[25]

In human brain tissue, regulation of HTR2A varies depending on the region:[18] 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.[18]

### Transcriptional regulation

There are a few mechanisms of regulation for HTR2A gene such regulated by DNA methylation at particular transcript binding sites.[26][27] 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.[28] These mRNA variants result in different isoforms which may have antagonistic functions or differential expression patterns, yielding plasticity and adaptability to the cells.[29] One study found that the common genetic variant rs6311 regulates expression of HTR2A transcripts containing the extended 5' UTR.[18]

## Tissue distribution

5-HT2A is expressed widely throughout the central nervous system (CNS).[30] 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[31][32][33] by enhancing glutamate release followed by a complex range of interactions with the 5-HT1A,[34] GABAA,[35] adenosine A1,[36] AMPA,[37] mGluR2/3,[38] mGlu5,[39] and OX2 receptors.[40][41] In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer,[42] and in the Purkinje cells.[43][44]

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.[45] Whole-body distribution of the 5-HT2A/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-HT2A receptor binding.[46]

## 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.[47][48] 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.[49][50] 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.[50][51] 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.[47][50] 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.[50] These structural features underlie the receptor's ability to recognize diverse ligands and mediate complex signaling behaviors.

The cryo-EM structures of the serotonin 5-HT2A receptor with a variety of serotonin 5-HT2A receptor agonists, including the tryptamines serotonin (neurotransmitter and endogenous agonist), psilocin (psychedelic), and dimethyltryptamine (DMT) (psychedelic), the lysergamides LSD (psychedelic) and 2-bromo-LSD (BOL-148) (non-hallucinogenic), and the phenethylamines mescaline (psychedelic) and RS130-180 (β-arrestin-biased agonist with unknown hallucinogenic potential), have been solved and published by Bryan Roth and colleagues.[52][53]

## 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.[54] It is highly expressed in the cerebral cortex, especially in layer V pyramidal neurons and certain interneurons, where it modulates thalamocortical information processing and may influence gamma oscillations, which are important for sensory integration and perception.[55] 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.[55] 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.[55][51] Activation of the 5-HT2A receptor by agonists is associated with enhanced cognition and hallucinogenic effects, while antagonists have antipsychotic and antidepressant properties.[54] Dysregulation of 5-HT2A receptor function has been implicated in psychiatric disorders such as depression, schizophrenia, and drug addiction.[54] 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.[55]

### 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.[56]

### 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-HT2A receptor agonists such as LSD, DMT, etc.[57][58]
* 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.[59][60]
* Activation of the 5-HT2A receptor in hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin.[61][62]
* Role in memory and learning.[33][63][64]
* Role in arthralgia.[65][66]
* Role in Alzheimer's disease.[67]
* Smooth muscle contraction in the gut.[2]
* Probable role in sleep paralysis.[58]
* Probable role in aging.[68][69]

## 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.[70][71] 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. Some findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT2A–mGlu2 and not by monomeric 5-HT2A receptors.[72][73][57] However, newer research suggests that 5HT2A and mGlu2 receptors do not physically associate with each other, so the former findings have questionable relevance.[74] Agonists enhance dopamine in PFC,[33] enhance memory and play an active role in attention and learning.[75][76]

Serotonin 5-HT2A receptor agonists include serotonergic psychedelics[77] and non-hallucinogenic agents.[78][79] Psychedelics have widely been encountered as recreational drug or drugs of misuse, with potential clinical consequences such as overdose, hospitalization, bad trips and worsened mental health, and rare adverse effects such as seizures, psychosis, and hallucinogen persisting perception disorder (HPPD).[80][81] 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, and addiction as well as other conditions like cluster headaches.[82][83][84][85][86] 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.[85][87][88]

#### 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 and in-vitro studies).[89][90][91][92][93][94][95] In contrast to corticosteroids however, psychedelics with anti-inflammatory effects do not appear to suppress the immune system.[89][90] Some psychedelics have been found to be far more potent in their anti-inflammatory effects than in their psychedelic effects.[91][92] 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.[91][92][90] Psilocin, the active form of psilocybin, has similar anti-inflammatory potency as (R)-DOI.[90][91][95]

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.[90][95] 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.[95][96][97] Hence, the psychedelic and anti-inflammatory effects of serotonin 5-HT2A receptor agonists appear to be fully dissociable.[95][96][97] These effects appear to be mediated by different intracellular signaling pathways, although the exact pathways are unclear.[97]

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.[98][99][100] They may also have applications in the treatment of neuroinflammation.[89][92] The anti-inflammatory effects of psychedelics might be involved in the claimed effects of psychedelic microdosing.[101][102] Relatedly, LSD microdosing is being studied in the treatment of Alzheimer's disease specifically for its anti-inflammatory effects.[103][104]

#### Full agonists

* 25B-NBOMe - also known as Cimbi-36; used as a PET imaging tool for visualizing the 5-HT2A receptor[105]
* 25I-NBOH and its 2-methoxy-analog 25I-NBOMe[106]
* BMB-202 - highly selective[107]
* 18F FECIMBI-36 - radiolabelled agonist ligand for mapping 5-HT2A / 5-HT2C receptor distribution[108]
* 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.[109]
* TCB-2[110]

#### Partial agonists

* 25C-NBOMe
* 25CN-NBOH - 100× selectivity for 5-HT2A over 5-HT2C, 46× selectivity over 5-HT2B.[111]
* 3-Carboxy indole PB-22 (1-pentyl-indole-3-carboxylic acid) - a metabolite of the synthetic cannabinoid PB-22, partial agonist at 5-HT2A[112]
* BMB-201 - non-hallucinogenic-like in animals[113]
* Bromo-DragonFLY[16]
* 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.[114]
* (R)-DOI - traditionally the most common 5-HT2A reference agonist used in research[115]
* Efavirenz - an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT2A.[116]
* IHCH-7113 - 5-HT2A agonist derived by simplification of the 5-HT2A antagonist antipsychotic lumateperone.[117]
* Lisuride - an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT2A / 5-HT2C agonist[118] and 5-HT2B antagonist.[119]
* Mefloquine - an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT2A and/or 5-HT2C receptors.[120]
* 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.[121]
* 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.[122][123][124][125][126]
* Substituted tetrahydro-β-carboline[127]
* Tetrahydropyridine derivatives such as (R)-69,[128] Z4154032166 and WXVL BT0793LQ2118.[129]
* Zalsupindole (DLX-001; AAZ-A-154) - non-hallucinogenic but retains antidepressant effects in animals.[130]

#### Selective agonists

* 25CN-NBOH[131][78]
* BMB-202[107]
* DMBMPP[78][132]
* LPH-5[133][134]
* LPH-48[135]
* Lysergine[78][136]
* O-4310[137][138]
* TGF-8027[139]

#### 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.[140] 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.[141]

### Antagonists

Serotonin 5-HT2A receptor antagonists, including many atypical antipsychotics, more selective agents like pimavanserin, and certain antidepressants and hypnotics like trazodone, mirtazapine, tricyclic antidepressants, and hydroxyzine, are used in the treatment of psychiatric disorders and other conditions such as depression, anxiety, psychosis, and insomnia.[142][143][144] Ketanserin, a dual serotonin 5-HT2A receptor antagonist and α1-adrenergic receptor antagonist, is used as an antihypertensive agent.[145][144] The non-selective serotonin 5-HT2A receptor antagonist cyproheptadine is frequently used off-label to treat serotonin syndrome, albeit based on limited clinical evidence.[146][147][148] Serotonin 5-HT2A receptor antagonists like ketanserin have been used as psychedelic antidotes or "trip killers" to manage the hallucinogenic effects of serotonergic psychedelics.[149][150][151]

#### List of antagonists

* 2-Alkyl-4-aryl-tetrahydro-pyrimido-azepines - subtype selective antagonists (35 g: 60-fold).[152]
* 5-MeO-NBpBrT
* AMDA and related derivatives - family of selective 5-HT2A antagonists.[153][154][155][156][157]
* 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).[158][159]
* 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.
* Lumateperone
* 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.[160]
* Trazodone - a potent 5-HT2A antagonist, as well as an antagonist on other serotonin receptors.
* Tetracyclic antidepressants - mianserin,[161] mirtazapine, maprotiline
* Tricyclic antidepressants (TCAs) - e.g., amitriptyline, nortriptyline, amoxapine, clomipramine, doxepin, maprotiline, imipramine, iprindole[161]
* Typical antipsychotics - e.g., haloperidol and chlorpromazine (minor)
* Volinanserin (MDL100907, M100907) - the most potent 5-HT2A antagonist;[162] 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.[163] As the receptor is present in coronary arteries[164] and capable of mediating vasoconstriction, 5-HT2A has also been linked to coronary artery spasms.[165] 5-HT antagonism, therefore, has potential in the prevention of cardiovascular disease, however, no studies have been published so far.[163]

### Inverse agonists

* AC-90179 - potent and selective inverse agonist at 5-HT2A, also 5-HT2C antagonist.[166][167]
* 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.[168]
* 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.[169][170][171][172][173]

### Positive allosteric modulators

Positive allosteric modulators of the serotonin 5-HT2A receptor have been identified.[174][175] These include CTW0404 and CTW0419.[174][175] They selectively potentiated the serotonin 5-HT2A receptor without affecting the serotonin 5-HT2B and 5-HT2C receptors.[174][175] 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 psychedelic effects.[174][175] Instead, they blunted the (R)-DOI-induced head-twitch response.[175] The (R)-enantiomer of glaucine has also been reported to be a serotonin 5-HT2A receptor positive allosteric modulator.[176] A dual serotonin 5-HT2C and 5-HT2A receptor positive allosteric modulator is the oleamide analogue JPC0323.[177][178]

### 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.[179]

120px 130px

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.[180][181] 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.[182][183] 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.[184]

### Serotonin-elevating drugs

Besides direct serotonin 5-HT2A receptor agonists, many drugs elevate serotonin levels and indirectly activate serotonin 5-HT2A receptors.[185][186] Examples include antidepressants 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).[185][186] 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.[187][188][189][190][191][192] Serotonin 5-HT2A receptor activation may be involved in the therapeutic effects of serotonin-elevating medications[185][186] and appears to be importantly involved in the subjective effects of SRAs like MDMA.[150] Serotonin-elevating drugs can cause serotonin syndrome 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.[193][194][195]

## Methods to analyse the receptor

### Neuroimaging

The 5-HT2A receptors may be imaged with PET-scanners using the fluorine-18-altanserin,[196] MDL 100,907[197] or [11C]Cimbi-36[105][198] 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.[199]

Altanserin uptake decreases with age reflecting a loss of specific 5-HT2A receptors with age.[200][201][202]

### 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.[2]

## Clinical significance

### Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as major depressive disorder.[203] and a strong link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia.[204]

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.[205] A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.[206]

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.[207]

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.[208][209] Exactly how these results translate over to further biopsychological understanding of schizophrenia is still widely debated.[210][211] There is some evidence that dysfunction of HTR2A can impact pharmacological interventions.[212]

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[213] but other studies failed to replicate these findings and found no association between polymorphism and suicidal behavior.[214]

#### Treatment response

Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.[215]

#### 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 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.[216] There are conflicting results as other studies have found associations between T102C polymorphisms alcohol misuse.[217][218]

#### Drug impact on gene expression

There is some evidence that methylation patterns may contribute to relapse behaviors in people who use stimulants.[219] In mice, psychotropic drugs such as DOI, LSD, DOM, and DOB which produced differing transcriptional patterns among several different brain regions.[209]

## See also

* Ultra-large-scale docking

## References

1. ↑ "Primary structure of the human platelet serotonin 5-HT2A receptor: identify with frontal cortex serotonin 5-HT2A receptor". Journal of Neurochemistry 63 (2): 465–469. August 1994. doi:10.1046/j.1471-4159.1994.63020465.x. PMID 8035173.
2. ↑ 2.0 2.1 2.2 Kling A (2013). 5-HT2A: a serotonin receptor with a possible role in joint diseases (PDF) (Ph.D. thesis). Umeå, Sweden: Umeå Universitet. ISBN 978-91-7459-549-9.
3. ↑ "Serotonin 2A (5-HT2A) Receptor Function: Ligand-Dependent Mechanisms and Pathways". Ishier. Frontiers in Neuroscience. Press/Taylor & Francis. 2007. ISBN 978-0-8493-3977-6.
4. ↑ 4.0 4.1 "Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists". Goodman & Gilman's the Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. 2006. ISBN 0-07-142280-3.
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6. ↑ Basic neurochemistry: molecular, cellular, and medical aspects. 1 (7th ed.). Academic Press. 2005. p. 241. ISBN 0-12-088397-X. https://books.google.com/books?id=Af0IyHtGCMUC&pg=PA241.
7. ↑ "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacology, Biochemistry, and Behavior 71 (4): 533–554. April 2002. doi:10.1016/S0091-3057(01)00746-8. PMID 11888546.
8. ↑ 8.0 8.1 8.2 "A suite of engineered mice for interrogating psychedelic drug actions". bioRxiv. September 2023. doi:10.1101/2023.09.25.559347. PMID 37808655. "The HTR2A was first identified by radioligand binding in 1978 (Leysen et al., 1978), was characterized as a membrane protein in 1985 (Wouters et al., 1985), and its encoding gene, Htr2a, was cloned in 1988 (Pritchett et al., 1988). The structure of Htr2a was characterized further by the Chen and Shih groups for human HTR2A and Toth group for murine Htr2a, who identified various introns, exons, and promoters (Chen et al., 1992; Shih et al., 1996; Toth, 1996).".
9. ↑ "Serotonergic component of neuroleptic receptors". Nature 272 (5649): 168–171. March 1978. doi:10.1038/272168a0. PMID 564466.
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11. ↑ "Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol". Mol Pharmacol 16 (3): 687–699. November 1979. doi:10.1016/S0026-895X(25)13812-1. PMID 530254.
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14. ↑ "[3H]-DOB(4-bromo-2,5-dimethoxyphenylisopropylamine) and [3H] ketanserin label two affinity states of the cloned human 5-hydroxytryptamine2 receptor". Mol Pharmacol 38 (5): 604–609. November 1990. doi:10.1016/S0026-895X(25)09519-7. PMID 2233697.
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17. ↑ "Fibromyalgia and Female Sexual Pain Disorders". Female Sexual Pain Disorders: Evaluation and Management (2 ed.). Wiley. 2020. ISBN 978-1-119-48266-6.
18. ↑ 18.0 18.1 18.2 18.3 "Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons". BMC Genetics 17 (1). January 2016. doi:10.1186/s12863-015-0325-6. PMID 26738766.
19. ↑ "Initiation of Behavioral Response to Antidepressants by Cholecystokinin Neurons of the Dentate Gyrus". Neuron 95 (3): 564–576.e4. August 2017. doi:10.1016/j.neuron.2017.06.044. PMID 28735749.
20. ↑ "Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome". Brain 140 (3): 669–683. March 2017. doi:10.1093/brain/aww342. PMID 28073790.
21. ↑ "How much do we know about the coupling of G-proteins to serotonin receptors?". Molecular Brain 7 (1). July 2014. doi:10.1186/s13041-014-0049-y. PMID 25011628.
22. ↑ "Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders". Genome Medicine 12 (1). March 2020. doi:10.1186/s13073-020-00725-6. PMID 32183904.
23. ↑ "HTR2A promotes the development of cardiac hypertrophy by activating PI3K-PDK1-AKT-mTOR signaling". Cell Stress & Chaperones 25 (6): 899–908. November 2020. doi:10.1007/s12192-020-01124-x. PMID 32519137.
24. ↑ "Food intake-related genes in chicken determined through combinatorial genome-wide association study and transcriptome analysis". Animal Genetics 51 (5): 741–751. October 2020. doi:10.1111/age.12980. PMID 32720725.
25. ↑ "Association of SNPs in dopamine and serotonin pathway genes and their interacting genes with temperament traits in Charolais cows". Journal of Applied Genetics 58 (3): 363–371. August 2017. doi:10.1007/s13353-016-0383-0. PMID 27987181.
26. ↑ "mRNA Expression and DNA Methylation Analysis of Serotonin Receptor 2A (HTR2A) in the Human Schizophrenic Brain". Genes 8 (1): 14. January 2017. doi:10.3390/genes8010014. PMID 28054990.
27. ↑ "Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association". Neuromolecular Medicine 13 (1): 66–76. March 2011. doi:10.1007/s12017-010-8138-2. PMID 20941551.
28. ↑ "Function of alternative splicing". Gene 514 (1): 1–30. February 2013. doi:10.1016/j.gene.2012.07.083. PMID 22909801.
29. ↑ "Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins". Genome Research 25 (6): 858–871. June 2015. doi:10.1101/gr.184390.114. PMID 25883322.
30. ↑ "A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System". The Journal of Neuroscience 37 (1): 120–128. January 2017. doi:10.1523/JNEUROSCI.2830-16.2016. PMID 28053035.
31. ↑ "Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release". Brain Research 825 (1–2): 161–171. April 1999. doi:10.1016/S0006-8993(99)01224-X. PMID 10216183.
32. ↑ "A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex". Neuroscience 105 (2): 379–392. 2001. doi:10.1016/S0306-4522(01)00199-3. PMID 11672605.
33. ↑ 33.0 33.1 33.2 "The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity". Journal of Neurochemistry 95 (6): 1597–1607. December 2005. doi:10.1111/j.1471-4159.2005.03485.x. PMID 16277612.
34. ↑ "Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex". Cerebral Cortex 14 (3): 281–299. March 2004. doi:10.1093/cercor/bhg128. PMID 14754868.
35. ↑ "Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons". The Journal of Neuroscience 21 (17): 6502–6511. September 2001. doi:10.1523/JNEUROSCI.21-17-06502.2001. PMID 11517239.
36. ↑ "Activation of adenosine(1) (A(1)) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats". Neuropharmacology 56 (8): 1082–1087. June 2009. doi:10.1016/j.neuropharm.2009.03.005. PMID 19324062.
37. ↑ "AMPA receptor involvement in 5-hydroxytryptamine2A receptor-mediated pre-frontal cortical excitatory synaptic currents and DOI-induced head shakes". Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (1): 62–71. January 2008. doi:10.1016/j.pnpbp.2007.07.009. PMID 17728034.
38. ↑ "Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors". Neuropsychopharmacology 23 (5): 569–576. November 2000. doi:10.1016/S0893-133X(00)00136-6. PMID 11027922.
39. ↑ "Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex". Neuroscience Letters 442 (3): 239–243. September 2008. doi:10.1016/j.neulet.2008.06.083. PMID 18621097.
40. ↑ "Schizophrenia, hypocretin (orexin), and the thalamocortical activating system". Schizophrenia Bulletin 33 (6): 1284–1290. November 2007. doi:10.1093/schbul/sbm088. PMID 17656637.
41. ↑ "Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy". Proceedings of the National Academy of Sciences of the United States of America 105 (1): 359–364. January 2008. doi:10.1073/pnas.0706679105. PMID 18172209. Bibcode: 2008PNAS..105..359L.
42. ↑ "Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum". Journal of Chemical Neuroanatomy 24 (1): 65–74. June 2002. doi:10.1016/S0891-0618(02)00020-0. PMID 12084412.
43. ↑ "Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells". Neuroscience Letters 252 (1): 72–74. August 1998. doi:10.1016/S0304-3940(98)00546-1. PMID 9756362.
44. ↑ "Expression of serotonin2A receptors in Purkinje cells of the developing rat cerebellum". Neuroscience Research 50 (4): 411–417. December 2004. doi:10.1016/j.neures.2004.08.010. PMID 15567478.
45. ↑ "5-Hydroxytryptamine modulates cytokine and chemokine production in LPS-primed human monocytes via stimulation of different 5-HTR subtypes". International Immunology 17 (5): 599–606. May 2005. doi:10.1093/intimm/dxh242. PMID 15802305.
46. ↑ "Human biodistribution and radiation dosimetry of the 5-HT2A receptor agonist Cimbi-36 labeled with carbon-11 in two positions". EJNMMI Research 9 (1). July 2019. doi:10.1186/s13550-019-0527-4. PMID 31367837.
47. ↑ 47.0 47.1 "Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties". PLOS Computational Biology 8 (4). 2012. doi:10.1371/journal.pcbi.1002473. PMID 22532793. Bibcode: 2012PLSCB...8E2473S.
48. ↑ ﻿The Serotonin G-Protein Coupled Receptor 5HT2A: Molecular and Multiple Sequence Analysis.﻿ (Report). https://www.msudenver.edu/wp-content/uploads/2021/07/Chalit_final.pdf.
49. ↑ "Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine". Nature Structural & Molecular Biology 26 (2): 121–128. February 2019. doi:10.1038/s41594-018-0180-z. PMID 30723326.
50. ↑ 50.0 50.1 50.2 50.3 "Molecular insights into the modulation of the 5HT2A receptor by serotonin, psilocin, and the G protein subunit Gqα". FEBS Letters 599 (6): 876–891. March 2025. doi:10.1002/1873-3468.15099. PMID 39865564.
51. ↑ 51.0 51.1 "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nature Communications 14 (1). December 2023. doi:10.1038/s41467-023-44016-1. PMID 38102107.
52. ↑ "The structural diversity of psychedelic drug actions revealed". Nature Communications 16 (1). March 2025. doi:10.1038/s41467-025-57956-7. PMID 40108183. Bibcode: 2025NatCo..16.2734G.
53. ↑ "Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias". University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center. September 2022. https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37. "Recently, there has been a resurgence in utilizing classical psychedelics to treat depression, addiction, anxiety disorders, and cluster headaches. The biological target of these compounds, and the route of its therapeutic actions, is the 5HT2A receptor (5HT2AR). It has been hypothesized that the hallucinations and therapeutic actions can be separated through biased agonism and G-protein activation. Here we present 8 new cryoEM structures covering all major compound classes for the 5HT2AR including a novel arrestin biased compound RS130-180. Utilizing the structural and functional data we noticed a correlation between ligand bias and the placement of the canonical "toggle-switch" tryptophan. These findings lead to a broader mechanistic understanding of 5HT2AR activation as well as potential for the development of biased ligands."
54. ↑ 54.0 54.1 54.2 "The role of serotonin 5-HT2A receptors in memory and cognition". Frontiers in Pharmacology 6: 225. 2015. doi:10.3389/fphar.2015.00225. PMID 26500553.
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58. ↑ 58.0 58.1 "The neuropharmacology of sleep paralysis hallucinations: serotonin 2A activation and a novel therapeutic drug". Psychopharmacology 235 (11): 3083–3091. November 2018. doi:10.1007/s00213-018-5042-1. PMID 30288594.
59. ↑ "Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency". The Journal of Pharmacology and Experimental Therapeutics 327 (2): 316–323. November 2008. doi:10.1124/jpet.108.143461. PMID 18708586.
60. ↑ "Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo". PLOS ONE 8 (10). 2013. doi:10.1371/journal.pone.0075426. PMID 24098382. Bibcode: 2013PLoSO...875426N.
61. ↑ "5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells". The Journal of Neuroscience 21 (10): 3572–3579. May 2001. doi:10.1523/JNEUROSCI.21-10-03572.2001. PMID 11331386.
62. ↑ "Evidence that 5-HT2A receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (−)DOI". The Journal of Neuroscience 22 (21): 9635–9642. November 2002. doi:10.1523/JNEUROSCI.22-21-09635.2002. PMID 12417689.
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86. ↑ "Psychedelic Commercialization: A Wide-Spanning Overview of the Emerging Psychedelic Industry". Psychedelic Medicine 1 (3): 150–165. September 2023. doi:10.1089/psymed.2023.0013. PMID 40046566.
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204. ↑ "Association between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. European Multicentre Association Study of Schizophrenia (EMASS) Group". Lancet 347 (9011): 1294–1296. May 1996. doi:10.1016/s0140-6736(96)90939-3. PMID 8622505.
205. ↑ "Association study of two polymorphisms of the serotonin-2A receptor gene and suicide attempts". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 147B (5): 645–649. July 2008. doi:10.1002/ajmg.b.30642. PMID 18163387.
206. ↑ Gene Overview of All Published Schizophrenia-Association Studies for HTR2A – SzGene database at Schizophrenia Research Forum.
207. ↑ "HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies". Current Medicinal Chemistry 14 (19): 2053–2069. 2007. doi:10.2174/092986707781368450. PMID 17691947.
208. ↑ "Htr2a Expression Responds Rapidly to Environmental Stimuli in an Egr3-Dependent Manner". ACS Chemical Neuroscience 6 (7): 1137–1142. July 2015. doi:10.1021/acschemneuro.5b00031. PMID 25857407.
209. ↑ 209.0 209.1 "Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine". Neuropsychopharmacology 37 (10): 2285–2298. September 2012. doi:10.1038/npp.2012.81. PMID 22692564.
210. ↑ "Alternative splicing in serotonergic system: Implications in neuropsychiatric disorders". Journal of Psychopharmacology 33 (11): 1352–1363. November 2019. doi:10.1177/0269881119856546. PMID 31210090. http://zaguan.unizar.es/record/84343.
211. ↑ "Common HTR2A variants and 5-HTTLPR are not associated with human in vivo serotonin 2A receptor levels". Human Brain Mapping 41 (16): 4518–4528. November 2020. doi:10.1002/hbm.25138. PMID 32697408.
212. ↑ "Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach". Neuropharmacology 105: 142–153. June 2016. doi:10.1016/j.neuropharm.2015.12.022. PMID 26764241.
213. ↑ "Association between serotonin 2A receptor genetic variations, stressful life events and suicide". Gene 658: 191–197. June 2018. doi:10.1016/j.gene.2018.03.023. PMID 29526601.
214. ↑ "Association study of seven polymorphisms in four serotonin receptor genes on suicide victims". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 141B (6): 669–672. September 2006. doi:10.1002/ajmg.b.30390. PMID 16856120.
215. ↑ "The pharmacogenetics of major depression: past, present, and future". Biological Psychiatry 62 (11): 1205–1207. December 2007. doi:10.1016/j.biopsych.2007.09.016. PMID 17949692.
216. ↑ "Alcohol misuse in emerging adulthood: Association of dopamine and serotonin receptor genes with impulsivity-related cognition". Addictive Behaviors 63: 29–36. December 2016. doi:10.1016/j.addbeh.2016.05.008. PMID 27399274.
217. ↑ "The CC genotype in HTR2A T102C polymorphism is associated with behavioral impulsivity in alcohol-dependent patients". Journal of Psychiatric Research 46 (1): 44–49. January 2012. doi:10.1016/j.jpsychires.2011.09.001. PMID 21930285.
218. ↑ "The association of A-1438G and T102C polymorphisms in HTR2A and 120 bp duplication in DRD4 with alcoholic dependence in a northeastern Brazilian male population". Gene Reports 21. December 2020. doi:10.1016/j.genrep.2020.100889.
219. ↑ "Methylation Patterns of the HTR2A Associate With Relapse-Related Behaviors in Cocaine-Dependent Participants". Frontiers in Psychiatry 11. 2020-06-10. doi:10.3389/fpsyt.2020.00532. PMID 32587535.

## Further reading

* "A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2". Journal of the American Chemical Society 136 (45): 16044–16054. November 2014. doi:10.1021/ja508394x. PMID 25314362. Bibcode: 2014JAChS.13616044P.

## External links

* "5-HT2A". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2320.

* 2A Receptor 5-HT2A+Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
* Human HTR2A genome location and HTR2A gene details page in the UCSC Genome Browser.
* Overview of all the structural information available in the PDB for UniProt: P28223 (5-hydroxytryptamine receptor 2A) at the PDBe-KB.

* v
* t
* e

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin-like

| Neurotransmitter|

| Adrenergic|

* α1 (A
* B
* D)
* α2 (A
* B
* C)
* β1
* β2
* β3

|

Purinergic|

* Adenosine (A1
* A2A
* A2B
* A3)
* P2Y (1
* 2
* 4
* 5
* 6
* 8
* 9
* 10
* 11
* 12
* 13
* 14)

Serotonin|

* (all but 5-HT3) 5-HT1 (A
* B
* D
* E
* F)
* 5-HT2 (A
* B
* C)
* 5-HT (4
* 5A
* 6
* 7)

Other|

* Acetylcholine (M1
* M2
* M3
* M4
* M5)
* Dopamine
* D1
* D2
* D3
* D4
* D5
* GHB receptor
* Histamine
* H1
* H2
* H3
* H4
* Melatonin (1A
* 1B
* 1C)
* TAAR (1
* 2
* 5
* 6
* 8
* 9)

Metabolites and
signaling molecules|

| Eicosanoid|

* CysLT (1
* 2)
* LTB4
* 1
* 2
* FPRL1
* OXE
* Prostaglandin
* DP (1
* 2), EP (1
* 2
* 3
* 4), FP
* Prostacyclin
* Thromboxane

|

Other|

* Bile acid
* Cannabinoid (CB1
* CB2, GPR (18
* 55
* 119))
* EBI2
* Estrogen
* Free fatty acid (1
* 2
* 3
* 4)
* Hydroxycarboxylic acids
* 1
* 2
* 3
* Lysophosphatidic acid (1
* 2
* 3
* 4
* 5
* 6)
* Lysophospholipid (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8)
* Oxoglutarate
* PAF
* Sphingosine-1-phosphate (1
* 2
* 3
* 4
* 5)
* Succinate

Peptide|

| Neuropeptide|

* B/W (1
* 2)
* FF (1
* 2)
* S
* Y (1
* 2
* 4
* 5)
* Neuromedin (B
* U (1
* 2))
* Neurotensin (1
* 2)

|

Other|

* Anaphylatoxin (C3a
* C5a)
* Angiotensin (1
* 2)
* Apelin
* Bombesin
* BRS3
* GRPR
* NMBR)
* Bradykinin (B1
* B2)
* Chemokine
* Cholecystokinin (A
* B)
* Endothelin
* A
* B
* Formyl peptide (1
* 2
* 3)
* FSH
* Galanin (1
* 2
* 3)
* Gonadotropin-releasing hormone (1
* 2)
* Ghrelin
* Kisspeptin
* Luteinizing hormone/choriogonadotropin
* MAS (1
* 1L
* D
* E
* F
* G
* X1
* X2
* X3
* X4)
* Melanocortin (1
* 2
* 3
* 4
* 5)
* MCHR (1
* 2)
* Motilin
* Opioid (Delta
* Kappa
* Mu
* Nociceptin & Zeta, but not Sigma)
* Orexin (1
* 2)
* Oxytocin
* Prokineticin (1
* 2)
* Prolactin-releasing peptide
* Relaxin (1
* 2
* 3
* 4)
* Somatostatin (1
* 2
* 3
* 4
* 5)
* Tachykinin (1
* 2
* 3)
* Thyrotropin
* Thyrotropin-releasing hormone
* Urotensin-II
* Vasopressin (1A
* 1B
* 2)

Miscellaneous|

| Taste, bitter|

* TAS2R
* 1
* 3
* 4
* 5
* 7
* 8
* 9
* 10
* 13
* 14
* 16
* 19
* 20
* 30
* 31
* 38
* 39
* 40
* 41
* 42
* 43
* 45
* 46
* 50
* 60
* Vomeronasal receptor type 1

|

Orphan|

* GPR (1
* 3
* 4
* 6
* 12
* 15
* 17
* 18
* 19
* 20
* 21
* 22
* 23
* 25
* 26
* 27
* 31
* 32
* 33
* 34
* 35
* 37
* 39
* 42
* 44
* 45
* 50
* 52
* 55
* 61
* 62
* 63
* 65
* 68
* 75
* 77
* 78
* 81
* 82
* 83
* 84
* 85
* 87
* 88
* 92
* 101
* 103
* 109A
* 109B
* 119
* 120
* 132
* 135
* 137B
* 139
* 141
* 142
* 146
* 148
* 149
* 150
* 151
* 152
* 153
* 160
* 161
* 162
* 171
* 173
* 174
* 176
* 177
* 182
* 183)

Other|

* Adrenomedullin
* Olfactory
* Opsin (3
* 4
* 5
* 1LW
* 1MW
* 1SW
* RGR
* RRH)
* Protease-activated (1
* 2
* 3
* 4)
* SREB (1
* 2
* 3)

Class B: Secretin-like

| Adhesion|

* ADGRG (1
* 2
* 3
* 4
* 5
* 6
* 7)

|

Orphan|

* GPR (56
* 64
* 97
* 98
* 110
* 111
* 112
* 113
* 114
* 115
* 116
* 123
* 124
* 125
* 126
* 128
* 133
* 143
* 144
* 155
* 157)

Other|

* Brain-specific angiogenesis inhibitor (1
* 2
* 3)
* Cadherin (1
* 2
* 3)
* Calcitonin
* CALCRL
* CD97
* Corticotropin-releasing hormone (1
* 2)
* EMR (1
* 2
* 3)
* Glucagon (GR
* GIPR
* GLP1R
* GLP2R)
* Growth-hormone-releasing hormone
* PACAPR1
* GPR
* Latrophilin (1
* 2
* 3
* ELTD1)
* Methuselah-like proteins
* Parathyroid hormone (1
* 2)
* Secretin
* Vasoactive intestinal peptide (1
* 2)

Class C: Metabotropic glutamate / pheromone

| Taste, sweet|

* TAS1R
* 1
* 2
* 3
* Vomeronasal receptor, type 2

|

Other|

* Calcium-sensing receptor
* GABAB (1
* 2)
* Glutamate receptor (Metabotropic glutamate (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8))
* GPRC6A
* GPR (156
* 158
* 179)
* RAIG (1
* 2
* 3
* 4)

Class F: Frizzled & Smoothened

| Frizzled|

* Frizzled (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8
* 9
* 10)

|

Smoothened|

* Smoothened

* v
* t
* e

Serotonin receptor modulators

5-HT1|

| 5-HT1A|

* Agonists: 8-OH-DPAT
* Adatanserin
* Amphetamine
* Antidepressants (e.g., etoperidone, hydroxynefazodone, nefazodone, trazodone, triazoledione, vilazodone, vortioxetine)
* Atypical antipsychotics (e.g., aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, lurasidone, quetiapine, ziprasidone)
* Azapirones (e.g., buspirone, eptapirone, gepirone, perospirone, tandospirone)
* Bay R 1531
* Befiradol
* BMY-14802
* Cannabidiol
* Dimemebfe
* Dopamine
* Ebalzotan
* Eltoprazine
* Enciprazine
* Ergolines (e.g., bromocriptine, cabergoline, dihydroergotamine, ergotamine, lisuride, LSD, methylergometrine (methylergonovine), methysergide, pergolide)
* F-11461
* F-12826
* F-13714
* F-14679
* F-15063
* F-15,599
* Flesinoxan
* Flibanserin
* Flumexadol
* Hypidone
* Lesopitron
* LY-293284
* LY-301317
* mCPP
* MKC-242
* Naluzotan
* NBUMP
* Osemozotan
* Oxaflozane
* Pardoprunox
* Piclozotan
* Rauwolscine
* Repinotan
* Roxindole
* RU-24,969
* S-14,506
* S-14671
* S-15535
* Sarizotan
* Serotonin (5-HT)
* SSR-181507
* Sunepitron
* Tryptamines (e.g., 5-CT, 5-MeO-DMT, 5-MT, bufotenin, DMT, indorenate, N-Me-5-HT, psilocin, psilocybin)
* TGBA01AD
* U-92,016-A
* Urapidil
* Vilazodone
* Xaliproden
* Yohimbine

* Antagonists: Atypical antipsychotics (e.g., iloperidone, risperidone, sertindole)
* AV965
* Beta blockers (e.g., alprenolol, carteolol, cyanopindolol, iodocyanopindolol, isamoltane, oxprenolol, penbutolol, pindobind, pindolol, propranolol, tertatolol)
* BMY-7,378
* CSP-2503
* Dotarizine
* Ergolines (e.g., metergoline)
* FCE-24379
* Flopropione
* GR-46611
* Isamoltane
* Lecozotan
* Mefway
* Metitepine (methiothepin)
* MIN-117 (WF-516)
* MPPF
* NAN-190
* Robalzotan
* S-15535
* SB-649,915
* SDZ 216-525
* Spiperone
* Spiramide
* Spiroxatrine
* UH-301
* WAY-100135
* WAY-100635
* Xylamidine

* Unknown/unsorted: Acetryptine
* Carvedilol
* Ergolines (e.g., ergometrine (ergonovine))

5-HT1B|

* Agonists: Anpirtoline
* CGS-12066A
* CP-93129
* CP-94253
* CP-122,288
* CP-135807
* Eltoprazine
* Ergolines (e.g., bromocriptine, dihydroergotamine, ergotamine, methylergometrine (methylergonovine), methysergide, pergolide)
* mCPP
* RU-24,969
* Serotonin (5-HT)
* Triptans (e.g., avitriptan, donitriptan, eletriptan, sumatriptan, zolmitriptan)
* TFMPP
* Tryptamines (e.g., 5-BT, 5-CT, 5-MT, DMT)
* Vortioxetine

* Antagonists: AR-A000002
* Beta blockers (e.g., alprenolol, carteolol, isamoltane, oxprenolol, penbutolol, propranolol, tertatolol)
* Elzasonan
* Ergolines (e.g., metergoline)
* GR-127935
* Isamoltane
* LY-393558
* Metitepine (methiothepin)
* SB-216641
* SB-224289
* SB-236057
* Yohimbine

* Unknown/unsorted: Ergolines (e.g., cabergoline, ergometrine (ergonovine), lisuride)

5-HT1D|

* Agonists: CP-122,288
* CP-135807
* CP-286601
* Ergolines (e.g., bromocriptine, cabergoline, dihydroergotamine, ergotamine, LSD, methysergide)
* Chemistry:GR-46611
* L-694247
* Chemistry:L-772405
* mCPP
* PNU-109291
* PNU-142633
* Serotonin (5-HT)
* TGBA01AD
* Triptans (e.g., almotriptan, avitriptan, donitriptan, [[Chemistry:Eleeletriptan, Frovatriptan|frovatriptan]], naratriptan, rizatriptan, sumatriptan, zolmitriptan)
* Tryptamines (e.g., 5-BT, 5-CT, 5-Et-DMT, 5-MT, 5-(nonyloxy)tryptamine, DMT)

* Antagonists: Alniditan
* BRL-15,572
* Elzasonan
* Ergolines (e.g., metergoline)
* GR-127935
* Ketanserin
* LY-310762
* LY-367642
* LY-393558
* LY-456219
* LY-456220
* Metitepine (methiothepin)
* Mianserin
* Ritanserin
* Yohimbine
* Ziprasidone

* Unknown/unsorted: Acetryptine
* Ergolines (e.g., lisuride, lysergol, pergolide)

5-HT1E|

* Agonists: BRL-54443
* Ergolines (e.g., methysergide)
* Serotonin (5-HT)
* Triptans (e.g., eletriptan)
* Tryptamines (e.g., tryptamine)

* Antagonists: Metitepine (methiothepin)

* Unknown/unsorted: ErgIrindaloneolines (e.g., ergometrine (ergonovine), lysergol, methylergometrine (methylergonovine)

5-HT1F|

* Agonists: BRL-54443
* CP-122,288
* Ergolines (e.g., bromocriptine, lysergol, methylergometrine (methylergonovine) methysergide)
* Lasmiditan
* LY-334370
* Serotonin (5-HT)
* Triptans (e.g., eletriptan, naratriptan, sumatriptan)
* Tryptamines (e.g., 5-MT)

* Antagonists: Metitepine (methiothepin)
* Mianserin

5-HT2|

| 5-HT2A|

* Agonists: 25H/NB series (e.g., 25I-NBF, 25I-NBMD, 25I-NBOH, 25I-NBOMe, 25B-NBOMe, 25C-NBOMe, 25TFM-NBOMe, 2CBCB-NBOMe, 25CN-NBOH, 2CBFly-NBOMe)
* 2Cs (e.g., 2C-B, 2C-E, 2C-I, 2C-T-2, 2C-T-7, 2C-T-21)
* 2C-B-FLY
* 2CB-Ind
* 5-Methoxytryptamines (5-MeO-DET, 5-MeO-DiPT, 5-MeO-DMT, 5-MeO-DPT, 5-MT)
* α-Alkyltryptamines (e.g., 5-Cl-αMT, 5-Fl-αMT, 5-MeO-αET, 5-MeO-αMT, α-Me-5-HT, αET, αMT)
* AL-34662
* AL-37350A
* Bromo-DragonFLY
* Dimemebfe
* DMBMPP
* DOx (e.g., DOB, DOC, DOI, DOM)
* Efavirenz
* Ergolines (e.g., 1P-LSD, ALD-52, bromocriptine, cabergoline, ergine (LSA), ergometrine (ergonovine), ergotamine, lisuride, LA-SS-Az, LSB, LSD, LSD-Pip, LSH, LSP, methylergometrine (methylergonovine), pergolide)
* Flumexadol
* IHCH-7113
* Jimscaline
* Lorcaserin
* MDxx (e.g., MDA (tenamfetamine), MDMA (midomafetamine), MDOH, MMDA)
* O-4310
* Oxaflozane
* PHA-57378
* PNU-22394
* PNU-181731
* RH-34
* SCHEMBL5334361
* Phenethylamines (e.g., lophophine, mescaline)
* Piperazines (e.g., BZP, quipazine, TFMPP)
* Serotonin (5-HT)
* TCB-2
* TFMFly
* Tryptamines (e.g., 5-BT, 5-CT, bufotenin, DET, DiPT, DMT, DPT, psilocin, psilocybin, tryptamine)

* Antagonists: 5-I-R91150
* 5-MeO-NBpBrT
* AC-90179
* Adatanserin
* Altanserin
* Antihistamines (e.g., cyproheptadine, hydroxyzine, ketotifen, perlapine)
* AMDA
* Atypical antipsychotics (e.g., amperozide, aripiprazole, asenapine, blonanserin, brexpiprazole, carpipramine, clocapramine, clorotepine, clozapine, fluperlapine, gevotroline, iloperidone, lurasidone, melperone, mosapramine, ocaperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zicronapine, ziprasidone, zotepine)
* Chlorprothixene
* Cinanserin
* CSP-2503
* Deramciclane
* Dotarizine
* Eplivanserin
* Ergolines (e.g., amesergide, LY-53857, LY-215,840, mesulergine, metergoline, methysergide, sergolexole)
* Fananserin
* Flibanserin
* Glemanserin
* Irindalone
* Ketanserin
* KML-010
* Landipirdine
* LY-393558
* mCPP
* Medifoxamine
* Metitepine (methiothepin)
* MIN-117 (WF-516)
* Naftidrofuryl
* Nantenine
* Nelotanserin
* Opiranserin (VVZ-149)
* Pelanserin
* Phenoxybenzamine
* Pimavanserin
* Pirenperone
* Pizotifen
* Pruvanserin
* Rauwolscine
* Ritanserin
* Roluperidone
* S-14671
* Sarpogrelate
* Serotonin antagonists and reuptake inhibitors (e.g., etoperidone, hydroxynefazodone, lubazodone, mepiprazole, nefazodone, triazoledione, trazodone)
* SR-46349B
* TGBA01AD
* Teniloxazine
* Temanogrel
* Tetracyclic antidepressants (e.g., amoxapine, aptazapine, esmirtazapine, maprotiline, mianserin, mirtazapine)
* Tricyclic antidepressants (e.g., amitriptyline)
* Typical antipsychotics (e.g., chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, pimozide, pipamperone, prochlorperazine, setoperone, spiperone, spiramide, thioridazine, thiothixene, trifluoperazine)
* Volinanserin
* Xylamidine
* Yohimbine

* Unknown/unsorted: Ergolines (e.g., dihydroergotamine, nicergoline)

5-HT2B|

* Agonists: 4-Methylaminorex
* Aminorex
* Amphetamines (e.g., chlorphentermine, cloforex, dexfenfluramine, fenfluramine, levofenfluramine, norfenfluramine)
* BW-723C86
* DOx (e.g., DOB, DOC, DOI, DOM)
* Ergolines (e.g., cabergoline, dihydroergocryptine, dihydroergotamine, ergotamine, methylergometrine (methylergonovine), methysergide, pergolide)
* Lorcaserin
* MDxx (e.g., MDA (tenamfetamine), MDMA (midomafetamine), MDOH, MMDA)
* Piperazines (e.g., TFMPP)
* PNU-22394
* Ro60-0175
* Serotonin (5-HT)
* Tryptamines (e.g., 5-BT, 5-CT, 5-MT, α-Me-5-HT, bufotenin, DET, DiPT, DMT, DPT, psilocin, psilocybin, tryptamine)

* Antagonists: Agomelatine
* Atypical antipsychotics (e.g., amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, N-desalkylquetiapine (norquetiapine), N-desmethylclozapine (norclozapine), olanzapine, pipamperone, quetiapine, risperidone, ziprasidone)
* Cyproheptadine
* EGIS-7625
* Ergolines (e.g., amesergide, bromocriptine, lisuride, LY-53857, LY-272015, mesulergine)
* Ketanserin
* LY-393558
* mCPP
* Metadoxine
* Metitepine (methiothepin)
* Pirenperone
* Pizotifen
* Propranolol
* PRX-08066
* Rauwolscine
* Ritanserin
* RS-127445
* Sarpogrelate
* SB-200646
* SB-204741
* SB-206553
* SB-215505
* SB-221284
* SB-228357
* SDZ SER-082
* Tegaserod
* Tetracyclic antidepressants (e.g., amoxapine, mianserin, mirtazapine)
* Trazodone
* Typical antipsychotics (e.g., chlorpromazine)
* TIK-301
* Yohimbine

* Unknown/unsorted: Ergolines (e.g., ergometrine (ergonovine))

5-HT2C|

* Agonists: 2Cs (e.g., 2C-B, 2C-E, 2C-I, 2C-T-2, 2C-T-7, 2C-T-21)
* 5-Methoxytryptamines (5-MeO-DET, 5-MeO-DiPT, 5-MeO-DMT, 5-MeO-DPT, 5-MT)
* α-Alkyltryptamines (e.g., 5-Cl-αMT, 5-Fl-αMT, 5-MeO-αET, 5-MeO-αMT, α-Me-5-HT, αET, αMT)
* A-372159
* AL-38022A
* Alstonine
* CP-809101
* Dimemebfe
* DOx (e.g., DOB, DOC, DOI, DOM)
* Ergolines (e.g., ALD-52, cabergoline, dihydroergotamine, ergine (LSA), ergotamine, lisuride, LA-SS-Az, LSB, LSD, LSD-Pip, LSH, LSP, pergolide)
* Flumexadol
* Lorcaserin
* MDxx (e.g., MDA (tenamfetamine), MDMA (midomafetamine), MDOH, MMDA)
* MK-212
* ORG-12962
* ORG-37684
* Oxaflozane
* PHA-57378
* Phenethylamines (e.g., lophophine, mescaline)
* Piperazines (e.g., aripiprazole, BZP, mCPP, quipazine, TFMPP)
* PNU-22394
* PNU-181731
* Ro60-0175
* Ro60-0213
* Serotonin (5-HT)
* Tryptamines (e.g., 5-BT, 5-CT, bufotenin, DET, DiPT, DMT, DPT, psilocin, psilocybin, tryptamine)
* Vabicaserin
* WAY-629
* WAY-161503
* YM-348

* Antagonists: Adatanserin
* Agomelatine
* Atypical antipsychotics (e.g., asenapine, clorotepine, clozapine, fluperlapine, iloperidone, melperone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, zotepine)
* Captodiame
* CEPC
* Cinanserin
* Cyproheptadine
* Deramciclane
* Desmetramadol
* Dotarizine
* Eltoprazine
* Ergolines (e.g., amesergide, bromocriptine, LY-53857, LY-215,840, mesulergine, metergoline, methysergide, sergolexole)
* Etoperidone
* Fluoxetine
* FR-260010
* Irindalone
* Ketanserin
* Ketotifen
* Latrepirdine (dimebolin)
* Medifoxamine
* Metitepine (methiothepin)
* Nefazodone
* Pirenperone
* Pizotifen
* Propranolol
* Ritanserin
* RS-102221
* S-14671
* SB-200646
* SB-206553
* SB-221284
* SB-228357
* SB-242084
* SB-243213
* SDZ SER-082
* Tedatioxetine
* Tetracyclic antidepressants (e.g., amoxapine, aptazapine, esmirtazapine, maprotiline, mianserin, mirtazapine)
* TIK-301
* Tramadol
* Trazodone
* Tricyclic antidepressants (e.g., amitriptyline, nortriptyline)
* Typical antipsychotics (e.g., chlorpromazine, loxapine, pimozide, pipamperone, thioridazine)
* Xylamidine

* Unknown/unsorted: Efavirenz
* Ergolines (e.g., ergometrine (ergonovine), methylergometrine (methylergonovine))

5-HT3–7|

| 5-HT3|

* Agonists: Alcohols (e.g., butanol, ethanol (alcohol), trichloroethanol)
* m-CPBG
* Phenylbiguanide
* Piperazines (e.g., BZP, mCPP, quipazine)
* RS-56812
* Serotonin (5-HT)
* SR-57227
* SR-57227A
* Tryptamines (e.g., 2-Me-5-HT, 5-CT, bufotenidine (5-HTQ))
* Volatiles/gases (e.g., halothane, isoflurane, toluene, trichloroethane)
* YM-31636

* Antagonists: Alosetron
* Chemistry:Arazasetron
* AS-8112
* Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine)
* Azasetron
* Batanopride
* Bemesetron (MDL-72222)
* Bupropion
* Cilansetron
* CSP-2503
* Dazopride
* Dolasetron
* Galanolactone
* Granisetron
* Hydroxybupropion
* Lerisetron
* Memantine
* Ondansetron
* Palonosetron
* Ramosetron
* Renzapride
* Ricasetron
* Tedatioxetine
* Tetracyclic antidepressants (e.g., amoxapine, mianserin, mirtazapine)
* Thujone
* Tropanserin
* Tropisetron
* Typical antipsychotics (e.g., loxapine)
* Volatiles/gases (e.g., nitrous oxide, sevoflurane, xenon)
* Vortioxetine
* Zacopride
* Zatosetron

* Unknown/unsorted: LY-53857
* Piperazines (e.g., naphthylpiperazine)

5-HT4|

* Agonists: 5-MT
* BIMU8
* Capeserod
* Cinitapride
* Cisapride
* CJ-033466
* Dazopride
* Metoclopramide
* Minesapride
* Mosapride
* Prucalopride
* PRX-03140
* Renzapride
* RS-67,333
* RS-67,506
* Serotonin (5-HT)
* Tegaserod
* Usmarapride
* Velusetrag
* Zacopride

* Antagonists: GR-113808
* GR-125487
* L-Lysine
* Piboserod
* RS-39604
* RS-67532
* SB-203186
* SB-204070

5-HT5A|

* Agonists: Ergolines (e.g., 2-Br-LSD (BOL-148), ergotamine, LSD)
* Serotonin (5-HT)
* Tryptamines (e.g., 5-CT)
* Valerenic acid

* Antagonists: Asenapine
* Latrepirdine (dimebolin)
* Metitepine (methiothepin)
* Ritanserin
* SB-699551

* Unknown/unsorted: Ergolines (e.g., metergoline, methysergide)
* Piperazines (e.g., naphthylpiperazine)

5-HT6|

* Agonists: Ergolines (e.g., dihydroergocryptine, dihydroergotamine, ergotamine, lisuride, LSD, mesulergine, metergoline, methysergide)
* Hypidone
* Serotonin (5-HT)
* Tryptamines (e.g., 2-Me-5-HT, 5-BT, 5-CT, 5-MT, Bufotenin, E-6801, E-6837, EMD-386088, EMDT, LY-586713, N-Me-5-HT, ST-1936, tryptamine)
* WAY-181187
* WAY-208466

* Antagonists: ABT-354
* Atypical antipsychotics (e.g., aripiprazole, asenapine, clorotepine, clozapine, fluperlapine, iloperidone, olanzapine, tiospirone)
* AVN-101
* AVN-211
* AVN-322
* AVN-397
* BGC20-760
* BVT-5182
* BVT-74316
* Cerlapirdine
* EGIS-12,233
* GW-742457
* Idalopirdine
* Ketanserin
* Landipirdine
* Latrepirdine (dimebolin)
* Masupirdine
* Metitepine (methiothepin)
* MS-245
* PRX-07034
* Ritanserin
* Ro 04-6790
* Ro 63-0563
* SB-258585
* SB-271046
* SB-357134
* SB-399885
* SB-742457
* Tetracyclic antidepressants (e.g., amoxapine, mianserin)
* Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, nortriptyline)
* Typical antipsychotics (e.g., chlorpromazine, loxapine)

* Unknown/unsorted: Ergolines (e.g., 2-Br-LSD (BOL-148), bromocriptine, lergotrile, pergolide)
* Piperazines (e.g., naphthylpiperazine)

5-HT7|

* Agonists: 8-OH-DPAT
* AS-19
* Bifeprunox
* E-55888
* Ergolines (e.g., LSD)
* LP-12
* LP-44
* LP-211
* RU-24,969
* Sarizotan
* Serotonin (5-HT)
* Triptans (e.g., frovatriptan)
* Tryptamines (e.g., 5-CT, 5-MT, bufotenin, N-Me-5-HT)

* Antagonists: Atypical antipsychotics (e.g., amisulpride, aripiprazole, asenapine, brexpiprazole, clorotepine, clozapine, fluperlapine, olanzapine, risperidone, sertindole, tiospirone, ziprasidone, zotepine)
* Butaclamol
* DR-4485
* EGIS-12,233
* Ergolines (e.g., 2-Br-LSD (BOL-148), amesergide, bromocriptine, cabergoline, dihydroergotamine, ergotamine, LY-53857, LY-215,840, mesulergine, metergoline, methysergide, sergolexole)
* JNJ-18038683
* Ketanserin
* LY-215,840
* Metitepine (methiothepin)
* Ritanserin
* SB-258719
* SB-258741
* SB-269970
* SB-656104
* SB-656104A
* SB-691673
* SLV-313
* SLV-314
* Spiperone
* Chemistry:SSR-181507
* Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin, mirtazapine)
* Tricyclic antidepressants (e.g., amitriptyline, clomipramine, imipramine)
* Typical antipsychotics (e.g., acetophenazine, chlorpromazine, chlorprothixene, fluphenazine, loxapine, pimozide)
* Vortioxetine

* Unknown/unsorted: Ergolines (e.g., lisuride, pergolide)
* Piperazines (e.g., naphthylpiperazine)

* See also: Receptor/signaling modulators
* Adrenergics
* Dopaminergics
* Melatonergics
* Monoamine reuptake inhibitors and releasing agents
* Monoamine metabolism modulators
* Monoamine neurotoxins

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