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5-HT receptor
The serotonin receptors also known as 5-hydroxytryptamine receptors or 5-HT receptors are
a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs) found in
the central and peripheral nervous systems.[1][2] They mediate both excitatory and inhibitory
neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin,
which acts as their natural ligand.
The serotonin receptors modulate the release of many neurotransmitters, including glutamate,
GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones,
including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others.
The serotonin receptors influence various biological and neurological processes such as
aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and
thermoregulation. The serotonin receptors are the target of a variety of pharmaceutical and illicit
drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic
agents, antimigraine agents, hallucinogens, and entactogens.[3]
Classification
With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other serotonin
receptors are G protein-coupled receptors that activate an intracellular second messenger cascade
to produce an excitatory or inhibitory response.
Families
Family Type
5-HT1 Gi/Go-protein coupled.
5-HT2 Gq/G11-protein coupled.
5-HT3
5-HT4
5-HT5
Ligand-gated Na+ and K+ cation
channel.
Gs-protein coupled.
Gi/Go-protein coupled.[4]
Mechanism
Decreasing cellular levels of cAMP.
Increasing cellular levels of IP3 and
DAG.
Potential
Inhibitory
Depolarizing plasma membrane.
Excitatory
Increasing cellular levels of cAMP.
Decreasing cellular levels of cAMP.
Excitatory
Inhibitory
Excitatory
5-HT6 Gs-protein coupled.
5-HT7 Gs-protein coupled.
Increasing cellular levels of cAMP.
Increasing cellular levels of cAMP.
Excitatory
Excitatory
[edit] Subtypes
Within these general classes of serotonin receptors, a number of specific types have been
characterized:
Rece
ptor
5HT1A
Gene(
s)
HTR1
A
Distribut
ion
Function
Agonists
Antagonists
Blood
Vessels
CNS
Addiction [8][9][10]
Aggression[11]
Anxiety[12]
Appetite[13]
Blood Pressure[14][15]
Cardiovascular
Function[16]
Emesis[17]
Heart Rate[14][15]
Impulsivity[18]
Memory[19][20]
Mood[21]
Nausea[17]
Nociception[22]
Penile Erection[23]
Pupil Dilation[24]
Respiration[25]
Sexual Behavior[26]
Sleep[27]
Sociability[28]
Thermoregulation[29]
Vasoconstriction[30]
5-CT
8-OH-DPAT
Aripiprazole
Buspirone[31] (anxiolytic
and antidepressant)[31]
Cannabidiol
Clozapine
Dihydroergotamine
Eltoprazine
Ergotamine
Flesinoxan
Flibanserin
Gepirone
Ipsapirone
Methysergide
Nefazodone
Quetiapine
RU 24969
Tandospirone
Trazodone
Urapidil
Xaliproden
Alprenolol
Asenapine
BMY 7378
Cyanopindolol
Iodocyanopindolol
Lecozotan
Methiothepin
NAN-190
Oxprenolol
Pindolol
Propanolol
Robalzotan
S15535
Spiperone
UH-301
WAY-100,135
WAY-100,635
5HT1B
HTR1
B
Blood
Vessels
CNS
Addiction [32]
Aggression[11]
Anxiety[33][34][35]
Learning[36]
Locomotion[37]
Memory[36]
Mood[35]
Penile Erection[23]
Sexual Behavior[26]
Vasoconstriction
5-CT
CP-93,129
CP-94,253
Dihydroergotamine
Eltoprazine
Ergotamine
Methysergide
RU 24969
TFMPP
Triptans[31]
(antimigraine[31])
Zolmitriptan
Eletriptan
Sumatriptan
Alprenolol
AR-A000002
Asenapine
Cyanopindolol
GR 127935
Iodocyanopindolol
Isamoltane
Metergoline
Methiothepin
Oxprenolol
Pindolol
Propanolol
SB-216,641
Yohimbine
5HT1D
HTR1
D
Blood
Vessels
CNS
Anxiety[38][39]
Locomotion[37]
Vasoconstriction
BRL-15572
GR 127935
Ketanserin
Metergoline
Methiothepin
Rauwolscine
Ritanserin
5HT1E
HTR1E Blood
Vessels
CNS
5-CT
Dihydroergotamine
Ergotamine
Methysergide
Triptans[31]
(antimigraine[31])
Almotriptan
Eletriptan
Frovatriptan
Naratriptan
Rizatriptan
Sumatriptan
Zolmitriptan
Yohimbine
Eletriptan
Methysergide
Tryptamine
5HT1F
HTR
1F
2C-B
5-MeO-DMT
BZP
Bufotenin
DMT
DOM
Ergonovine
Lisuride
LSD
Mescaline
Myristicin
Psilocin
Psilocybin
TFMPP
Atypical
antipsychotics
Clozapine[31]
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Aripiprazole
Asenapine
Cyproheptadine
Eplivanserin
Etoperidone
Iloperidone
Ketanserin[31]
Blood
Vessels
CNS
GI Tract
Platelets
PNS
Smooth
Muscle
Addiction
(potentially
modulating) [40]
Anxiety[41]
Appetite
Cognition
Imagination
Learning
Memory
Mood
Perception
Sexual Behavior[42]
Sleep[43]
Thermoregulation[44]
Methiothepin
Vasoconstriction[45]
Yohimbine
(antihypertensive[31]
)
Methysergide
Mianserin
Mirtazapine
Nefazodone
Pimavanserin
Pizotifen
Ritanserin
Trazodone
5HT2A
HTR2
A
Blood
Vessels
CNS
GI Tract
Platelets
PNS
Smooth
Muscle
Addiction (potentially
modulating) [40]
Anxiety[41]
Appetite
Cognition
Imagination
Learning
Memory
Mood
Perception
Sexual Behavior[42]
Sleep[43]
Thermoregulation[44]
Vasoconstriction[45]
2C-B
5-MeO-DMT
BZP
Bufotenin
DMT
DOM
Ergonovine
Lisuride
LSD
Mescaline
Myristicin
Psilocin
Psilocybin
TFMPP
Yohimbine
Atypical
antipsychotics
Clozapine[31]
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Aripiprazole
Asenapine
Cyproheptadine
Eplivanserin
Etoperidone
Iloperidone
Ketanserin[31]
(antihypertensive[31])
Methysergide
Mianserin
Mirtazapine
Nefazodone
Pimavanserin
Pizotifen
Ritanserin
Trazodone
5HT2B
HTR2
B
Blood
Vessels
CNS
GI Tract
Platelets
PNS
Smooth
Muscle
Anxiety[46][47][48]
Appetite[49]
Cardiovascular
Function
GI Motility[50]
Sleep[43]
Vasoconstriction
BW-723C86
Fenfluramine
MDMA
Norfenfluramine
Ro60-0175
Agomelatine
Asenapine
BZP
Ketanserin
Methysergide
Ritanserin
Tegaserod
Yohimbine
5HT2
HTR2
C
Blood
Vessels
CNS
A-372,159
AL-38022A
Aripiprazole
Agomelatine[31]
(antidepressant[31])
Asenapine
C
Addiction.
(potentially
GI Tract
Platelets
PNS
Smooth
Muscle
modulating)[40]
Anxiety[51][52][53]
Appetite
GI Motility[54]
Locomotion
Mood[53][52]
Penile Erection[55][56]
Sexual Behavior[42]
Sleep[57]
Thermoregulation[44]
Vasoconstriction
Ergonovine
Lorcaserin
Ro60-0175
TFMPP
Trazodone[31]
(hypnotic[31])
YM-348
Clozapine[31]
(antipsychotic[31])
Cyproheptadine
Dimebolin
Eltoprazine
Etoperidone
Fluoxetine
Iloperidone
Ketanserin[31]
(antihypertensive[31]
)
Lisuride
Methysergide[58]
Mianserin
Mirtazapine
Nefazodone
Olanzapine
Quetiapine
Risperidone
Ritanserin
Trazodone
Alosetron
Several
antiemetics[31]
Dolasetron
Ondansetron[31]
Granisetron
Tropisetron
Clozapine
Memantine
Metoclopramide
Mianserin
Mirtazapine
Olanzapine
Quetiapine
L-Lysine[60]
Piboserod
5HT3
HTR3 CNS
A
GI Tract
HTR3 PNS
B
HTR3
C
HTR3
D
HTR3E
Addiction
Anxiety
Emesis
GI Motility
Learning[59]
Memory[59]
Nausea
2-Methyl-5-HT
BZP
Quipazine
RS-56812
5HT4
HTR4
Anxiety[60][61]
Appetite[62][63]
GI Motility
Learning[64][65]
Memory[66][65][67]
Mood[68][69]
Respiration[70]
5-MT
BIMU-8
Cinitapride
Cisapride[31]
(gastroprokinetic)
Dazopride
Metoclopramide
Mosapride
Prucalopride
RS-67333
Renzapride
Tegaserod
CNS
GI Tract
PNS
5HT5A
HTR5
A
CNS
Locomotion[71]
Sleep[72]
5-CT
Ergotamine
Valerenic Acid[72]
Asenapine
Dimebolin
Methiothepin
Ritanserin
SB-699,551
SB-699,551-A
5HT6
HTR6
CNS
Anxiety[73][74]
Cognition[75]
Learning[76]
Memory[76]
Mood[74][77]
EMD-386,088
EMDT
Aripiprazole
Asenapine
Clozapine
Dimebolin
EGIS-12233
Iloperidone
MS-245
Olanzapine
Ro04-6790
SB-258,585
SB-271,046[78]
SB-357,134
SB-399,885
5HT7
HTR7
Blood
Vessels
CNS
GI Tract
Anxiety[79][80]
Memory[81][82]
Mood[79][80]
Respiration[25][83]
Sleep[79][83][84]
Thermoregulation
Vasoconstriction
5-CT
8-OH-DPAT
AS-19
Aripiprazole
Asenapine
Clozapine
EGIS-12233
Iloperidone
Ketanserin
Olanzapine
Ritanserin
SB-269,970
Note that there is no 5-HT1C receptor since, after the receptor was cloned and further
characterized, it was found to have more in common with the 5-HT2 family of receptors and was
redesignated as the 5-HT2C receptor. Note that there is also no 5-HT5B receptor, as it exists only
in mice and rats and not in humans or monkeys.
Very nonselective agonists of 5-HT receptor subtypes include ergotamine (an antimigraine),
which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors.[31] LSD (a
psychedelic) is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist.[31]
Serotonin (5-hydroxytryptamine, 5-HT) is a key mediator in the physiology of mood, vascular
function and gastrointestinal motility. This explains the number of therapeutic agents that act
targeting the serotonergic system such as: 5-HT3 antagonists, SSRIs and triptans.
This post will focus on the classification of serotonin receptors, as well as drug classes that act
on serotonergic transmission. This includes 5-HT agonists, antagonists and medications that
modulate 5-HT at the presynaptic level, all of them of very high clinical relevance. Overdose of a
combitation of serotonergic agents can lead to serotonin syndrome.
Outline:




Serotonin receptors
Drugs acting on serotonergic transmission: MAO inhibitors, SNRIs, SSRIs
Serotonin agonists
Serotonin antagonists
Serotonin receptors classification
Based on biochemical and pharmacological criteria, serotonin receptors are classified into seven
main receptor subtypes, 5-HT1–7. Of major pharmacotherapeutic importance are those
designated 5-HT1, 5-HT2, 5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the
5-HT3 subtype represents a ligand-gated ion channel.
5-HT1 receptors are subdivided into 5-HT1A, 5-HT1B, and 5-HT1D receptors; while 5-HT2
subtypes include 5-HT2A, 5-HT2B, and 5-HT2C.
Drugs acting on serotonergic transmission
The figure
above depicts how serotonin neurotransmission may be modified at the presynaptic level by
inhibiting degradation, storage or reuptake.
MAO inhibitors
Monoamine oxidase is a key enzyme for serotonin, dopamine and norepinephrine inactivation.
MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess
neurotransmitter to diffuse into the synaptic space. This class of agents is used in the treatment of
depression (phenelzine, tranylcypromine, selegiline) and Parkinson’s disease (selegiline).
Dietary restrictions (because of tyramine toxicity) limit their widespread use.
Inhibitors of serotonin storage
They interfere withe the ability of synaptic vesicles to store monoamines; displace serotonin,
dopamine and norepinephrine from their storage in presynaptic nerve terminals. Agents that
share this mechanism of action include amphetamine, methylphenidate and modafinil.
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
SNRIs mechanism involves blockade of 5-HT and norepinephrine reuptake in a concentrationdependent manner. Agents in this class include venlafaxine and duloxetine, they may be
effective for the treatment of depression in patients in whom SSRIs are ineffective.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs block the reuptake of serotonin, leading to increased concentrations of the
neurotransmitter in the synaptic cleft and to an enhanced postsynaptic neuronal activity.
Tricyclic-antidepressants (TCAs)
Tricyclic antidepressants act by inhibiting reuptake of 5-HT and norepinephrine from the
synaptic cleft by respectively blocking 5-HT and norepinephrine reuptake transporters, thereby
causing enhancement of postsynaptic response.
Serotonin receptor agonists
Serotonin receptors agonists have wide clinical applications, from treatment of depression to
abortive medications for migraine headache. According to the receptor they activate, they can be
divided into:
5-HT1A agonists
Buspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and
depression.
5-HT1B and 5-HT1D agonists
The “triptans” are a drug class useful as abortive medication for the treatment of acute migraine
headaches. They are very effective medications that bind to 5-HT1B and 5-HT1D receptors in
cranial vessels, which leads to vasoconstriction and decreased release of neuropeptides involved
in “sterile inflammation”.
5-HT2C agonist
Trazodone was previously believed to be a 5-HT2C receptor antagonist. However, recent
publications report that trazodone would behave as a 5-HT2C agonist. This drug is used
generally as somnorific.
5-HT4 agonists
Cisapride is a serotonin and cholinergic agonist used as a prokinetic drug, it was withdrawn from
the U.S. market because of cardiovascular toxicity.
Non-selective agonists
Ergotamine activates a more than one subtype of 5-HT receptor, it binds to 5-HT1A, 5-HT1D,
5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable
treatment for migraine attacks.
LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic
properties.
Serotonin receptor antagonists
5-HT2 antagonists
Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. In addition to its
serotonin antagonism, it has affinity for alpha-1 receptors, which may contribute to its
antihypertensive effect.
Clozapine is an atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high
affinity for dopamine receptors. It represents a class of atypical antipsychotic drugs, one key
advantage of this group is its reduced incidence of extrapyramidal side effects compared to the
classical antipsychotics, and possibly a greater efficacy for reducing negative symptoms of
schizophrenia.
Agomelatine is a new antidepressant with agonist action at the melatonin receptor and
antagonism at the 5-HT2C receptor.
5-HT3 antagonists
This class includes drugs such as ondansetron, palonosetron and others. These agents are
particularly useful in the treatment of chemotherapy induced nausea and vomiting (CINV).
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