The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that
belongs to the serotonin receptor family and is a G protein-coupled receptor.
This is the main excitatory receptor subtype among the GPCRs for serotonin,
although 5-HT2A may also have an inhibitory effect on certain areas such
as the visual cortex and the orbitofrontal cortex. This receptor was
first given importance as a target of serotonergic psychedelic drugs such as
LSD. Later it came back to prominence because it was also found to be
mediating, at least partly, the action of many antipsychotic drugs, especially
the atypical ones. 5-HT2A may be a necessary receptor for
the spread of the human polyoma virus called JC virus.
Downregulation of post-synaptic 5-HT2A receptor is an adaptive process provoked
by chronic administration of selective serotonin reuptake inhibitors and
classical antipsychotics. Deceased suicidal and otherwise depressed
patients have had more 5-HT2A receptors than normal patients. These findings
suggest that post-synaptic 5-HT2A overdensity is involved in the
pathogenesis of depression. History
Serotonin receptors were split into two classes by Gaddum and Picarelli when it
was discovered that some of the serotonin-induced changes in the gut
could be blocked by morphine, whilst the remainder of the response was inhibited
by dibenzyline leading to the naming of M and D receptors respectively. 5-HT2A
is thought to correspond to what was originally described as D subtype of
5-HT receptors by Gaddum and Picarelli. In the pre-molecular-cloning era when
radioligand binding and displacement was the only major tool, spiperone and LSD
were shown to label two different serotonin receptors, and neither of them
displaced morphine, leading to naming of the 5-HT1, 5-HT2 and 5-HT3 receptors,
corresponding to high affinity sites from LSD, spiperone and morphine
respectively. Later it was shown that the 5-HT2 was very close to 5-HT1C and
thus were clubbed together, renaming the 5-HT2 into 5-HT2A. Thus the 5-HT2
receptor family is composed of three separate molecular entities: the 5-HT2A,
the 5-HT2B and the 5-HT2C receptors. Distribution
5-HT2A is expressed widely throughout the central nervous system. It is
expressed near most of the serotoninergic terminal rich areas,
including neocortex and the olfactory tubercle. Especially high concentrations
of this receptor on the apical dendrites of pyramidal cells in layer V of the
cortex may modulate cognitive processes, working memory,and attention by
enhancing glutamate release followed by a complex range of interactions with the
5-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 system, in fibroblasts, and in neurons of the peripheral nervous
system. Additionally, 5-HT2A mRNA expression has been observed in human
monocytes. 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
activity, which subsequently promotes the release of diacylglycerol and
inositol triphosphate, which in turn stimulate protein kinase C activity and
Ca2+ release. There are many additional signal cascade
components that include the formation of arachidonic acid through PLA2 activity,
activation of phospholipase D, Rho/Rho kinase, and ERK pathway activation
initiated by agonist stimulation of the receptor.
Effects Physiological processes mediated by the
receptor include: CNS: neuronal excitation, behavioural
effects, learning, anxiety smooth muscle: contraction
vasoconstriction / vasodilation platelets: aggregation
Activation of the 5-HT2A receptor with 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. Activation of the 5-HT2A receptor in
hypothalamus causes increases in hormonal levels of oxytocin, prolactin,
ACTH, corticosterone, and renin. Role in memory
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. Agonists acting at 5-HT2A receptors
located on the apical dendrites of pyramidal cells within regions of the
prefrontal cortex are believed to mediate hallucinogenic activity. Newer
findings reveal that psychoactive effects of classic psychedelics are
mediated by the receptor heterodimer 5-HT2A–mGlu2 and not by monomeric 5-HT2A
receptors. Agonists enhance dopamine in PFC,enhances memory and plays a role in
attention and learning. Full agonists
25I-NBOH and its 2-methoxy-analog 25I-NBOMe
(R)-DOI TCB-2
Bromo-DragonFLY Mexamine is a full agonist to several
serotonin receptors. O-4310, 5-HT2A selective, claimed to
have 100x selectivity over 5-HT2C and be inactive at 5-HT2B
PHA-57378, dual 5-HT2A / 5-HT2C agonist, anxiolytic effects in animal studies.
Partial agonists 25C-NBOMe
Methysergide, a congener of methylergonovine, used in treatment of
migraine blocks 5-HT2A and 5-HT2C receptors, but sometimes acts as partial
agonist, in some preparations. OSU-6162 acts as a partial agonist at
both 5-HT2A and dopamine D2 receptors 25CN-NBOH, 100x selectivity for 5-HT2A
over 5-HT2C, 46x selectivity over 5-HT2B.
Juncosamine, is a structurally constrained derivative of 25B-NBOMe,
which acts as a potent partial agonist with 124x selectivity for 5-HT2A over
5-HT2C, making it the most selective agonist ligand identified to date.
Cannabidiol, a phytocannabinoid in Cannabis.
Efavirenz, an antiretroviral drug, produces psychiatric side effects
thought to be mediated by 5-HT2A. Mefloquine, an antimalarial drug, also
produces psychiatric side effects which may be mediated through 5-HT2A and/or
5-HT2C receptors. Lisuride, an antiparkinson dopamine
agonist of the ergoline class, that is also a dual 5-HT2A / 5-HT2C agonist and
5-HT2B antagonist. 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.
= Silent antagonists= Trazodone is a potent 5-HT2A antagonist,
as well as an antagonist on other serotonin receptors.
Although ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, a
few ergot derivatives such as metergoline bind preferentially to
members of the 5-HT2 receptor family. The discovery of Ketanserin was a
landmark in the pharmacology of 5-HT2 receptors. Ketanserin, though capable of
blocking 5-HT induced platelet adhesion, however does not mediate its well known
antihypertensive action through 5-HT2 receptor family, but through its high
affinity for alpha1 adrenergic receptors. It also has high affinity for
H1 histaminergic receptors equal to that at 5-HT2A receptors. Compounds
chemically related to ketanserin such as ritanserin are more selective 5-HT2A
receptor antagonists with low affinity for alpha-adrenergic receptors. However,
ritanserin, like most other 5-HT2A receptor antagonists, also potently
inhibits 5-HT2C receptors. Nefazodone operates by blocking
post-synaptic serotonin type-2A receptors and to a lesser extent by
inhibiting pre-synaptic serotonin and norepinephrine reuptake.
Atypical antipsychotic drugs like clozapine, olanzapine, quetiapine,
risperidone and asenapine are relatively potent antagonists of 5-HT2A as are some
of the lower potency old generation/typical antipsychotics. Other
antagonists are MDL-100,907 and cyproheptadine.
Pizotifen is a non-selective antagonist. LY-367,265 - dual 5-HT2A antagonist /
SSRI with antidepressant effects lkyl-4-aryl-tetrahydro-pyrimido-azepines
are subtype selective antagonists. AMDA and related derivatives are another
family of selective 5-HT2A antagonists. Hydroxyzine
5-MeO-NBpBrT = Inverse agonists=
AC-90179 - potent and selective inverse agonist at 5-HT2A, also 5-HT2C
antagonist. Nelotanserin - 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. Eplivanserin, a sleeping pill that
reached phase II trials, acts as a selective 5-HT2A inverse agonist.
Pimavanserin - more selective than AC-90179, orally active, antipsychotic
in vivo, now in human clinical trials. Volinanserin
= Functional selectivity= 5-HT2A-receptor ligands may
differentially activate the transductional pathways. 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 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. = Role of lipophilicity=
A set of ligands were evaluated. For agonists, a highly significant linear
correlation was observed between binding affinity and lipophilicity. For ligands
exhibiting partial agonist or antagonist properties, the lipophilicity was
consistently higher than would be expected for an agonist of comparable
affinity. Genetics
The 5-HT2A receptors is coded by the HTR2A gene. In humans the gene is
located on chromosome 13. The gene has previously been called just HTR2 until
the description of two related genes HTR2B and HTR2C. Several interesting
polymorphisms have been identified for HTR2A: A-1438G, C102T and His452Tyr.
Many more polymorphisms exist for the gene. A 2006 paper listed 255.
= Associations with psychiatric disorders=
Several studies have seen links between the -1438G/A polymorphism and mood
disorders, such as bipolar disorder and major depressive disorder. A weak link
with an odds ratio of 1.3 has been found between the T102C polymorphism and
schizophrenia. This polymorphism has also been studied in relation to suicide
attempts, with a study finding excess of the C/C genotypes among the suicide
attempters. A number of other studies were devoted to finding an association
of the gene with schizophrenia, with diverging results.
These individual studies may, however, not give a full picture: A review from
2007 looking at the effect of different SNPs reported in separate studies stated
that "genetic association studies [of HTR2A gene variants with psychiatric
disorders] report conflicting and generally negative results" with no
involvement, small or a not replicated role for the genetic variant of the
gene. Treatment response
One study has found that genetic variations between individuals in the
HTR2A gene may to some extent account for the difference in outcome of
antidepressant treatment, so that patients suffering from major depressive
disorder and treated with Citalopram may benefit more than others if they have
one particular genotype. In this study 768 single nucleotide polymorphism
across 68 genes were investigated and a SNP—termed rs7997012—in the second
intron of the HTR2A gene showed significant association with treatment
outcome. Genetics seems also to be associated to
some extent with the amount of adverse events in treatment of major depression
disorder. One study has also linked abnormal
5-HT2A polymorphisms which may enhance receptor activity with Chronic Fatigue
Syndrome. Neuroimaging
The 5-HT2A receptors may be imaged with PET-scanners using the
fluorine-18-altanserin and MDL 100,907 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.
Another PET study reported increased altanserin binding in the caudate nuclei
in obsessive compulsive disorder patients compared to a healthy control
group. Patients with Tourette's syndrome have
also been scanned and the study found an increased binding of altanserin for
patients compared to healthy controls. The altanserin uptake decreases with age
reflecting a loss of specific 5-HT2A receptors with age. A study has also
found a positive correlation among healthy subjects between altanserin
binding and the personality trait neuroticism as measured by the NEO PI-R
personality questionnaire. Role in virus endocytosis
5-HT2A may be a necessary receptor for clathrin mediated endocytosis of the
human polyoma virus called JC virus, the causative agent of progressive
multifocal leukoencephalopathy, that enters cells such as oligodendrocytes,
astrocytes, B lymphocytes, and kidney epithelial cells. These cells need to
express both the alpha 2-6–linked sialic acid component of the 5-HT2A receptor in
order to endocytose JCV. References
Further reading Perez-Aguilar JM, Shan J, LeVine MV,
Khelashvili G, Weinstein H. "A functional selectivity mechanism at the
serotonin-2A GPCR involves ligand-dependent conformations of
intracellular loop 2". J. Am. Chem. Soc. 136: 16044–16054. doi:10.1021/ja508394x.
PMID 25314362. External links
"5-HT2A". IUPHAR Database of Receptors and Ion Channels. International Union of
Basic and Clinical Pharmacology. 5-HT2A Receptor at the US National
Library of Medicine Medical Subject Headings