The mammalian
5-HT2A receptor is a subtype of the 5-HT
2 receptor which belongs to the serotonin receptor family and is a G protein coupled receptor (GPCR). This is the main excitatory receptor subtype among the GPCRs for
serotoninSerotonin is a monoamine neurotransmitter. It is found extensively in the gastrointestinal tract of animals, and about 80 to 90 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements...
(5-HT), although 5-HT
2A may also have an inhibitory effect on certain areas such as the
visual cortexThe term visual cortex refers to the primary visual cortex and extrastriate visual cortical areas such as V2, V3, V4, and V5. The primary visual cortex is anatomically equivalent to Brodmann area 17, or BA17...
and the
orbitofrontal cortexThe orbitofrontal cortex is a region of association cortex of the human brain involved in cognitive processes such as decision-making. The name of this region is based upon the region's location within the frontal lobes, resting above the orbits of the eyes...
. This receptor was given importance first as the target of
psychedelicThe term psychedelic is derived from the Greek words ψυχή and δηλείν , translating to "mind-manifesting". A psychedelic experience is characterized by the perception of aspects of one's mind previously unknown, or by the creative exuberance of the mind liberated from its ostensibly ordinary fetters...
drugs like
LSDLysergic acid diethylamide, LSD-25, LSD, formerly lysergide, commonly known as acid, is a semisynthetic psychedelic drug of the ergoline family...
. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many
antipsychoticAntipsychotics are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Over time a wide range of antipsychotics have been developed...
drugs, especially the
atypicalThe atypical antipsychotics are a group of antipsychotic drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
ones.
5-HT
2A also happens to be a necessary receptor for the spread of the human polyoma virus called
JC virusThe JC virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named after the two initials of a patient with progressive multifocal leukoencephalopathy...
.
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
morphineMorphine is a highly potent opiate analgesic psychoactive drug, is the principal active ingredient in Papaver somniferum , is considered to be the prototypical opioid. Like other opioids, e.g...
, whilst the remainder of the response was inhibited by
dibenzylinePhenoxybenzamine is a non-specific, irreversible alpha blocker.-Uses:It is used in the treatment of hypertension, and specifically that caused by pheochromocytoma...
leading to the naming of M and D receptors respectively. 5-HT
2A is thought to correspond to what was originally described as D subtype of 5-HT receptors by Gaddum and Picarelli. In the pre-molecular-cloning era when
radioligandA radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
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-HT1The 5-HT1 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin...
,
5-HT2The 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin...
and
5-HT3The 5-HT3 receptor is a member of the superfamily of ligand-gated ion channels, a superfamily that also includes the neuronal nicotinic acetylcholine receptors , and the inhibitory neurotransmitter receptors for GABA and glycine...
receptors, corresponding to high affinity sites from
LSDLysergic acid diethylamide, LSD-25, LSD, formerly lysergide, commonly known as acid, is a semisynthetic psychedelic drug of the ergoline family...
,
spiperoneSpiperone is a psychoactive drug and research chemical of the butyrophenone chemical class. It functions as a 5-HT
1A, 5-HT
2A, 5-HT
7, and D
2 receptor antagonist, and has been used to identify these receptors when labeled with tritium. It has negligible...
and morphine respectively. Later it was shown that the 5-HT
2 was very close to 5-HT
1C and thus were clubbed together, renaming the 5-HT
2 into 5-HT
2A. Thus the 5-HT
2 receptor family is comprised of three separate molecular entities: the 5-HT
2A (erstwhile 5-HT
2 or D), the 5-HT
2B (erstwhile 5-HT
2F) and the 5-HT
2C (erstwhile 5-HT
1C) receptors.
Distribution
5-HT
2A is expressed widely throughout the
central nervous systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
(CNS).
It is expressed near most of the serotoninergic terminal rich areas, including
neocortexThe neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
(mainly prefrontal, parietal, and somatosensory cortex) and the olfactory tubercle. Especially high concentrations of this receptor on the
apical dendriteAn apical dendrite is a dendrite that emerges from the apex of a pyramidal cell. Apical dendrites are one of two primary categories of dendrites, and they distinguish the pyramidal cells from spiny stellate cells in the cortices. Pyramidal cells are found in the prefrontal cortex, the hippocampus,...
s of
pyramidal cellPyramidal neurons are a type of neuron found in areas of the brain including cerebral cortex, the hippocampus, and in the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons were first discovered and...
s in layer V of the cortex may modulate cognitive processes, by enhancing glutamate release followed by a complex range of interactions with the
5-HT1AThe 5-HT1A receptor is a subtype of 5-HT receptor which binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor which is coupled to Gi/Go and mediates inhibitory neurotransmission...
, GABA
A, adenosine A
1,
AMPAThe α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog, AMPA...
, mGluR
2/3,
mGlu5Metabotropic glutamate receptor 5 is a protein that in humans is encoded by the GRM5 gene.-Ligands:In addition to the orthosteric site at least two distinct allosteric binding sites exist on the mGluR5...
, and
OX2Hypocretin receptor 2, also known as OX2, is a human protein encoded by the HCRTR2 gene.-Antagonists:* Almorexant - mixed OX1/2 antagonist* SB-649,868 - mixed OX1/2 antagonist...
receptors. In the rat cerebellum, the protein has also been found in the
Golgi cellIn neuroscience, Golgi cells are inhibitory interneurons found within the granular layer of the cerebellum. These cells synapse onto the soma of granule cells and unipolar brush cells. They receive excitatory input from mossy fibres, also synapsing on granule cells, and parallel fibers, which are...
s of the
granular layerThe term granular layer may refer to:*the granular layer of Tomes, seen in dentin of the teeth. When dry section of the root dentin of teeth are visualized under transmitted light, a granular layer is seen adjacent to cementum.It is believed to be caused by coalescing & looping of terminal portion...
, and in the
Purkinje cellFor the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
s.
In the periphery, it is highly expressed in platelets and many cell types of the cardiovascularsystem, in
fibroblastA fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s, and in neurons of the peripheral nervous system.
Signaling cascade
The 5-HT
2A receptor is known primarily to couple to the Gα
q signal transduction pathway. Upon receptor stimulation with agonist, Gα
q and β-γ subunits dissociate to initiate downstream effector pathways. Gα
q stimulates
phospholipase CPhosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC) activity, which subsequently promotes the release of
diacylglycerolA diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
(DAG) and
inositol triphosphateInositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol, is a secondary messenger molecule used in signal transduction and Lipid signaling in biological cells...
(IP3), which in turn stimulate
protein kinase CProtein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC) activity and Ca
2+ release.
There are many additional signal cascade components that include the formation of
arachidonic acidArachidonic acid is an omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is an omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA,...
through PLA2 activity, activation of
PLDPLD may refer to:Technology* Personal Locating Device, an implantable microchip that allows for an individual to be tracked remotely by use of GPS technology* Programmable Logic Device, a type of integrated circuit semiconductor...
,
RhoThe Rho family of GTPases is a family of small signaling G protein , and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic organisms including yeasts and some plants...
/
Rho kinaseRho kinase is a serine/threonine-specific protein kinase which is activated by GTP-bound RhoA. Rho kinase phosphorylates many substrate proteins and controls a wide variety of cellular functions, including smooth muscle contraction and proliferation, angiogenesis and synaptic remodelling....
, and
ERKERK can be:* an aircraft maintenance person * extracellular signal-regulated kinase - a type of Mitogen-activated protein kinase* a political party in Uzbekistan, 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 (in gastrointestinal tract
The human gastrointestinal tract , digestive tract, guts or gut is the system of organs within humans that takes in food, digests it to extract energy and nutrients, and expels the remaining matter...
& bronchi)
- vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
/ vasodilatation
- platelets: aggregation
- Activation of the 5-HT2A receptor with DOI produces superpotent anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids which affect the brain.-Medications:...
effecs in cardiovascular related tissues, as well as potent anti-inflammatory effects in non-cardiovascular tissues. Other 5-HT2A agonists like LSD also have potent anti-inflammatory effects against TNF-alpha induced inflammationInflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a...
.
Agonists
Activation of the 5-HT
2A receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
is necessary for the effects of the "classic" hallucinogens like
LSDLysergic acid diethylamide, LSD-25, LSD, formerly lysergide, commonly known as acid, is a semisynthetic psychedelic drug of the ergoline family...
,
psilocinPsilocin sometimes also spelled psilocine, psilocyn, or psilotsin, is a psychedelic mushroom alkaloid. It is found in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin. Psilocin is a Schedule I drug under the Convention on Psychotropic Substances...
and
mescalineMescaline or 3,4,5-trimethoxyphenethylamine is a naturally occurring psychedelic alkaloid of the phenethylamine class. It is mainly used as an entheogen, and a tool to supplement various practices for transcendence, including in meditation, psychonautics, art projects, and psychedelic...
, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT
2A agonists, the
ergolineErgoline is a chemical compound whose structural skeleton is contained in a diverse range of alkaloids including a few psychedelic drugs...
s,
tryptamineTryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...
s and
phenethylaminePhenethylamine is a natural monoamine alkaloid, trace amine, and psychoactive drug with stimulant effects. In the mammalian central nervous system, phenethylamine is believed to function as a neuromodulator or neurotransmitter. It is biosynthesized from the amino acid phenylalanine by enzymatic...
s, respectively. A very large family of derivatives from these three classes has been developed, and their
structure-activity relationshipStructure-activity relationships are the traditional practices of medicinal chemistry which try to modify the effect or the potency of bioactive chemical compounds by modifying their chemical structure...
s have been extensively researched. Agonists acting at 5-HT
2A receptors located on the
apical dendriteAn apical dendrite is a dendrite that emerges from the apex of a pyramidal cell. Apical dendrites are one of two primary categories of dendrites, and they distinguish the pyramidal cells from spiny stellate cells in the cortices. Pyramidal cells are found in the prefrontal cortex, the hippocampus,...
s of
pyramidal cellPyramidal neurons are a type of neuron found in areas of the brain including cerebral cortex, the hippocampus, and in the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons were first discovered and...
s within regions of the
prefrontal cortexThe prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
are believed to mediate hallucinogenic activity.
Full agonists
- (R)-DOI
2,5-dimethoxy-4-iodoamphetamine is a psychedelic drug and a substituted amphetamine of the phenethylamine family. Despite being a substituted amphetamine it is not a stimulant. DOI has a stereocenter and R--DOI is the more active stereoisomer...
- N-(2-hydroxybenzyl)-2C-I
25I-NBOH or N--1--2-aminoethane is a derivative of the phenethylamine derived hallucinogen 2C-I, discovered in 2006 by a team at Purdue University. It acts as a potent agonist for the 5HT2A receptor with a Ki of 0.12nM at the human 5HT2A receptor, making it some 5x the potency...
and its 2-methoxy-analog25I-NBOMe is a derivative of the phenethylamine hallucinogen 2C-I, discovered in 2004 by Ralf Heim at the Free University of Berlin, and subsequently investigated in more detail by a team at Purdue University led by David Nichols...
- TCB-2
TCB-2 is a conformationally restricted derivative of the phenethylamine derived hallucinogen 2C-B, discovered in 2006 by a team at Purdue University. It acts as a potent agonist for the 5HT
2A and 5HT
2C receptors with a Ki of 0.26nM at the human 5HT
2A receptor...
- Br-DFLY.
Partial agonists
MethysergideMethysergide is a prescription drug used for prophylaxis of migraine headaches and is sold under the brand names Sansert and Deseril in 2mg dosages.-Pharmacology:...
, a congener of
methylergonovineMethylergometrine is a synthetic analogue of ergonovine, a psychedelic alkaloid found in ergot, and many species of morning glory. It is a member of the ergoline family and chemically similar to LSD, ergine, ergometrine, and lysergic acid...
, used in treatment of
migraineMigraine is a neurological syndrome characterized by altered bodily perceptions, severe headaches, and nausea. Physiologically, the migraine headache is a neurological condition more common to women than to men. The word migraine was borrowed from Old French migraigne...
blocks 5-HT
2A and 5-HT
2C receptors, but sometimes acts as partial agonist, in some preparations.
Peripherally selective agonists
One effect of 5-HT
2A receptor activation is a reduction in intraocular pressure, and so 5-HT
2A agonists can be useful for the treatment of
glaucomaGlaucoma is a group of diseases that affect the optic nerve and involves a loss of retinal ganglion cells in a characteristic pattern. It is a type of optic neuropathy. Raised intraocular pressure is a significant risk factor for developing glaucoma...
. This has led to the development of compounds such as
AL-34662AL-34662 is an indazole derivative drug which is being developed for the treatment of glaucoma. It acts as a selective 5-HT
2A receptor agonist, the same target as that of hallucinogenic drugs like psilocin, but unlike these drugs, AL-34662 was designed specifically as a peripherally...
which are hoped to reduce pressure inside the eyes but without crossing the
blood-brain barrierThe blood-brain barrier is a separation of circulating blood and cerebrospinal fluid maintained by the choroid plexus in the central nervous system . Endothelial cells restrict the diffusion of microscopic objects The blood-brain barrier (BBB) is a separation of circulating blood and...
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
- Although ergot
Ergot refers to a group of fungi of the genus Claviceps . The most prominent member of this group is Claviceps purpurea. This fungus grows on rye and related plants, and can cause ergotism in humans and other mammals consuming seeds contaminated with the fruiting structure of this fungus, called an...
alkaloids are mostly nonspecific 5-HT receptor antagonists, a few ergot derivatives such as metergolineMetergoline is a synthetic compound, that acts on subsets of both 5-HT receptors and dopamine receptors. Metergoline has been reported to be a 5-HT
1D receptor agonist....
bind preferentially to members of the 5-HT2 receptor family.
- Ketanserin
Ketanserin is drug with affinity for multiple GPCR receptors. Initially it was believed to be a highly selective antagonist for serotonin 5-HT2A receptors, however this not true. Ketanserin only has weak selectivity for 5-HT2A receptors over 5-HT2C receptors...
, the prototypic 5-HT2 receptor antagonist potently blocks 5-HT2Areceptors, less potently blocks 5-HT2C receptors, and has no significant effect on 5-HT3 or 5-HT4 receptors or any members of the 5-HT1 receptor family. Thus 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 ritanserinRitanserin is a serotonin antagonist with wide-reaching possibilities for the treatment of many neurological disorders.When used together with typical antipsychotics in the treatment of schizophrenia is able to decrease negative symptoms and adds some "atypicality" as parkinsonism is slightly...
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
Nefazodone is a psychoactive drug and antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death...
operates by blocking post-synaptic serotonin type-2A receptors and to a lesser extent by inhibiting pre-synaptic serotonin and norepinephrine (noradrenaline) reuptake.
- Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
drugs like clozapineClozapine is an antipsychotic medication used in the treatment of schizophrenia...
, olanzapineOlanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
, quetiapineQuetiapine fumarate , marketed by AstraZeneca as Seroquel or SeroquelXR and by Orion Pharma as Ketipinor, is an atypical antipsychotic used in the management of schizophrenia, bipolar I mania, bipolar II depression, bipolar I depression, and used off-label for a variety of other purposes,...
, risperidoneRisperidone is an atypical antipsychotic used to treat schizophrenia , the mixed and manic states associated with bipolar disorder, and irritability in children with autism...
are relatively potent antagonists of 5-HT2A as are some of the lower potency old generation/typical antipsychotics. Other antagonists are MDL-100,907 (prototype of another new series of 5-HT2Aantagonists) and cyproheptadineCyproheptadine is an antihistaminic/anticholinergic and antiserotonergic agent...
.
- Pizotifen
Pizotifen or pizotyline , trade name Sandomigran, is a benzocycloheptane based drug used as a medicine, primarily as a preventative to reduce the frequency of recurrent migraine headaches.-Uses:...
is a non-selective antagonist.
- 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines are subtype selective antagonists (35g: 60-fold).
- AMDA
AMDA is an organic compound which acts as a potent and selective antagonist for the 5-HT2A receptor. It has been used to help study the shape of the 5-HT2A protein, and develop a large family of related derivatives with even higher potency and selectivity.- References :...
and related derivatives are another family of selective 5-HT2A antagonists.
Inverse agonistIn pharmacology, an inverse agonist is an agent which binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors. Inverse agonists exert the opposite pharmacological effect of a receptor agonist. Inverse agonists are effective against...
s
- AC-90179 - potent and selective inverse agonist at 5-HT2A, also 5-HT2C antagonist.
- APD-125 - selective 5-HT2A inverse agonist developed by Arena Pharmaceuticals
Arena Pharmaceuticals, Inc. is a biopharmaceutical company located in San Diego, California. The company is developing oral medications that target G-protein-coupled receptors. Currently none of the drugs is approved by the U.S...
for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials, but development of APD-125 was halted in December 2008 because the substance did not meet the trial's endpoints.
- Eplivanserin
Eplivanserin is an experimental drug for the treatment of insomnia, developed by Sanofi Aventis. , it is undergoing Phase III clinical trials.-Mechanism of action:...
(Sanofi Aventis), a new sleeping pill under development, acts as a selective 5-HT2A inverse agonist.
- Pimavanserin (ACP-103)
Pimavanserin is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A, with 10x selectivity over 5-HT2C, and no significant affinity or activity at 5-HT2B or dopamine receptors...
- more selective than AC-90179, orally active, antipsychotic in vivo, now in human clinical trials.
Examples
AgonistAn agonist is a drug that binds to a receptor of a cell and triggers a response by the cell. An agonist often mimics the action of a naturally occurring substance.An agonist produces an action...
s |
Antagonist An antagonist is a character, group of characters, or an institution, who represents the opposition against which the protagonist must contend...
s |
- α-methyl-5-HT
- AMT
- DMT
Dimethyltryptamine is a naturally-occurring tryptamine and potent psychedelic drug, found not only in many plants, but also in trace amounts in the human body where its natural function is undetermined. Structurally, it is analogous to the neurotransmitter serotonin and other psychedelic...
- LSD
Lysergic acid diethylamide, LSD-25, LSD, formerly lysergide, commonly known as acid, is a semisynthetic psychedelic drug of the ergoline family...
- mescaline
Mescaline or 3,4,5-trimethoxyphenethylamine is a naturally occurring psychedelic alkaloid of the phenethylamine class. It is mainly used as an entheogen, and a tool to supplement various practices for transcendence, including in meditation, psychonautics, art projects, and psychedelic...
- psilocin
Psilocin sometimes also spelled psilocine, psilocyn, or psilotsin, is a psychedelic mushroom alkaloid. It is found in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin. Psilocin is a Schedule I drug under the Convention on Psychotropic Substances...
- TCB-2
TCB-2 is a conformationally restricted derivative of the phenethylamine derived hallucinogen 2C-B, discovered in 2006 by a team at Purdue University. It acts as a potent agonist for the 5HT 2A and 5HT 2C receptors with a Ki of 0.26nM at the human 5HT 2A receptor...
|
cyproheptadineCyproheptadine is an antihistaminic/anticholinergic and antiserotonergic agent...
ketanserinKetanserin is drug with affinity for multiple GPCR receptors. Initially it was believed to be a highly selective antagonist for serotonin 5-HT2A receptors, however this not true. Ketanserin only has weak selectivity for 5-HT2A receptors over 5-HT2C receptors...
mirtazapineMirtazapine is a psychoactive drug of the benzazepine and tetracyclic antidepressant chemical classes which is used primarily as an antidepressant. It is sometimes also used as an anxiolytic, hypnotic, antiemetic, orexigenic, and antihistamine or antipruritic. Mirtazapine was introduced by...
nefazodoneNefazodone is a psychoactive drug and antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death...
pizotifenPizotifen or pizotyline , trade name Sandomigran, is a benzocycloheptane based drug used as a medicine, primarily as a preventative to reduce the frequency of recurrent migraine headaches.-Uses:...
trazodoneTrazodone is a psychoactive drug of the piperazine and triazolopyridine chemical classes that has anti depressant anxiolytic, and hypnotic properties...
atypical antipsychotics |
Functional selectivity
5-HT
2A-receptor
ligandsIn biochemistry and pharmacology, a ligand is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as...
may differentially activate the
transductional pathwaysIn biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another. Most processes of signal transduction involve ordered sequences of biochemical reactions inside the cell, which are carried out by enzymes and activated by second messengers,...
(see above). Studies evaluated the activation of two
effectorsAn effector is a molecule that binds to a protein and thereby alters the activity of that protein. A modulator molecule binds to a regulatory site during allosteric modulation and allosterically modulates the shape of the protein.- Types of effectors :* Activators* Inhibitors....
,
PLCPhosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
and
PLA2Phospholipases A2 are enzymes that releasefatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...
, by means of their second messengers. Compounds displaying more pronounced
functional selectivityFunctional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
are 2,5-DMA and
2C-N2C-N, or 2,5-Dimethoxy-4-nitrophenethylamine, is a psychedelic phenethylamine of the 2C family. It was first synthesized by Alexander Shulgin.-Chemistry:The full name of the chemical is 2-ethanamine....
. The former induces
IPInositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol, is a secondary messenger molecule used in signal transduction and Lipid signaling in biological cells...
accumulation without activating the PLA2 mediated response, while the latter elicits
AAArachidonic acid is an omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is an omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA,...
release without activating the PLC mediated response.
Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT
2A agonists that produce headshakes in the
mouseA mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. The American white-footed mouse and the deer mouse also sometimes live in houses. In some places, certain kinds of field mice are also common...
and those that do not, such as
lisurideLisuride is an anti-Parkinson's drug of the iso-ergoline class, chemically related to the dopaminergic ergoline Parkinson's drugs. Lisuride is described as free base and as hydrogenmaleate salt....
, as these agents are also non-hallucinogenic in humans despite being active 5-HT
2A agonists.
The difference in signal transduction between the two 5-HT
2A agonists serotonin and
DOI2,5-dimethoxy-4-iodoamphetamine is a psychedelic drug and a substituted amphetamine of the phenethylamine family. Despite being a substituted amphetamine it is not a stimulant. DOI has a stereocenter and R--DOI is the more active stereoisomer...
may be due to the presence of the intracellular proteins called β-
arrestinArrestins are a small family of proteins important for regulating signal transduction.-Function:Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors . In response to a stimulus, GPCRs activate heterotrimeric G proteins...
s, more specifically
arrestin beta 2Arrestin, beta 2, also known as ARRB2, is a human gene that codes an intracellular protein β-arrestin-2.Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G protein-coupled receptors and cause specific dampening of cellular responses...
.
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-HT
2A receptors is coded by the
HTR2A gene.
In humans the gene is located on chromosome 13.
The gene has previously been called just HTR2 until the description of two related genes
HTR2B and
HTR2C.
Several interesting
polymorphismPolymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
s have been identified for HTR2A:
A-1438G (
rs6311In genetics rs6311 is a gene variation—a single nucleotide polymorphism —in the human HTR2A gene that codes for the 5-HT2A receptor....
),
C102T (
rs6313In genetics, rs6313 also called T102C or C102T is a gene variation—a single nucleotide polymorphism —in the human HTR2A gene that codes for the 5-HT2A receptor....
) and
His452Tyr (
rs6314In genetics, rs6314, also called His452Tyr or H452Y, is a gene variation, a single nucleotide polymorphism , in the HTR2A gene that codes for the 5-HT2A receptor....
).
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 disorderBipolar disorder, also known as manic depressive disorder, manic depression or bipolar affective disorder, is a serious mental disorder that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if...
and major depressive disorder.
A weak link with an
odds ratioThe odds ratio is a measure of effect size, describing the strength of association or non-independence between two binary data values. It is used as a descriptive statistic, and plays an important role in logistic regression...
of 1.3 has been found between the T102C polymorphism and
schizophreniaSchizophrenia , from the Greek roots skhizein and phrēn, phren- is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality...
.
This polymorphism has also been studied in relation to
suicideSuicide is the intentional killing of one's self. Many dictionaries also note the metaphorical sense of "willful destruction of one's self-interest"...
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
CitalopramCitalopram is an antidepressant drug used to treat major depression associated with mood disorders. It is also used on occasion in the treatment of body dysmorphic disorder and anxiety....
may benefit more than others if they have one particular genotype.
In this study 768
single nucleotide polymorphismA single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C, or G — in the genome differs between members of a species...
(SNP) across 68 genes were investigated and a SNP—termed
rs7997012In genetics, rs7997012 is a gene variation—a single nucleotide polymorphism —in intron 2 of the human HTR2A gene that codes for the 5-HT2A receptor....
—in the second
intronAn intron is a DNA region within a gene that is not translated into protein. These non-coding sections are transcribed to precursor mRNA and some other RNAs , and subsequently removed by a process called splicing during the processing to mature RNA. After intron splicing An intron is a DNA region...
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.
Neuroimaging
The 5-HT
2A receptors may be imaged with PET-scanners using the fluorine-18-
altanserinAltanserin is a compound that binds to the 5-HT
2A receptor .It is a yellowish solid.Labeled with the isotope fluorine-18 it is used as a radioligand in positron emission tomography studies of the brain, i.e., studies of the serotonin-2A neuroreceptors.Besides human neuroimaging studies...
and MDL 100,907
radioligandA radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
s that binds to the neuroreceptor, e.g.,
one study reported a
reduced binding of altanserin particularly in the
hippocampusThe hippocampus is a major component of the brains of humans and other mammals. It belongs to the limbic system and plays important roles in long-term memory and spatial navigation. Like the cerebral cortex, with which it is closely associated, it is a paired structure, with mirror-image halves in...
in patients with major depressive disorder.
Another PET study reported
increased altanserin binding in the
caudate nucleiThe caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
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-HT
2A receptors with age.
A study has also found a positive correlation among healthy subjects between altanserin binding and the personality trait
neuroticismNeuroticism is a fundamental personality trait in the study of psychology. It can be defined as an enduring tendency to experience negative emotional states. Individuals who score high on neuroticism are more likely than the average to experience such feelings as anxiety, anger, guilt, and clinical...
as measured by the NEO PI-R personality questionnaire.
Role In virus endocytosis
5-HT
2A is a necessary receptor for
clathrinClathrin is a protein which plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape which is composed of three clathrin heavy chains and three light chains...
mediated
endocytosisEndocytosis is the process by which cells absorb molecules from outside the cell by engulfing it with their cell membrane. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma membrane or cell membrane...
of the human polyoma virus called
JC virusThe JC virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named after the two initials of a patient with progressive multifocal leukoencephalopathy...
, the causative agent of
progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations...
(PML), that enters cells like
oligodendrocyteOligodendrocytes , or oligodendroglia , are a variety of neuroglia. Their main function is the insulation of the axons exclusively in the central nervous system of the higher vertebrates, a function performed by Schwann cells in the peripheral nervous system...
s,
astrocyteAstrocytes are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a...
s, B lymphocytes, and kidney epithelial cells. These cells need to express both the alpha 2-6–linked
sialic acidSialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
component of the 5HT
2A receptor in order to endocytose JCV.
External links