5-HT receptors

5-HT receptors

            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. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand. The 5-HT1B receptor as an example of a metabotropic serotonin receptor.
            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 drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.
            Serotonin receptors are found in almost all animals and are even known to regulate longevity and behavioral aging in the primitive nematode, Caenorhabditis elegans.
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. In 2014 a novel 5-HT receptor was described that was isolated from the small white butterfly, Pieris rapae, and named pr5-HT8. It shares relatively low similarity to the known 5-HT receptor classes and does not occur in mammals.
Families
Family
Type
Mechanism
Potential
5-HT1
Gi/Go-protein coupled.
Decreasing cellular levels of cAMP.
Inhibitory
5-HT2
Gq/G11-protein coupled.
Increasing cellular levels of IP3 and DAG.
Excitatory
5-HT3
Ligand-gated Na+ and K+ cation channel.
Depolarizing plasma membrane.
Excitatory
5-HT4
Gs-protein coupled.
Increasing cellular levels of cAMP.
Excitatory
5-HT5
Gi/Go-protein coupled.
Decreasing cellular levels of cAMP.
Inhibitory
5-HT6
Gs-protein coupled.
Increasing cellular levels of cAMP.
Excitatory
5-HT7
Gs-protein coupled.
Increasing cellular levels of cAMP.
Excitatory




Subtypes
The 7 general serotonin receptor classes include a total of 14 known serotonin receptors.[8] The specific types have been characterized as follows:
Overview of Serotonin Receptors
Receptor
(first cloned)
Gene(s)
Distribution
Function
Agonists
Antagonists
Uses of drugs that act on this receptor
5-HT1A
(1987)
·                     HTR1A
·                     Blood Vessels
·                     CNS
·                     Addiction
·                     Aggression
·                     Anxiety
·                     Appetite
·                     Autoreceptor
·                     Blood Pressure
·                     Cardiovascular Function
·                     Emesis
·                     Heart Rate
·                     Impulsivity
·                     Memory
·                     Mood
·                     Nausea
·                     Nociception
·                     Penile Erection
·                     Pupil Dilation
·                     Respiration
·                     Sexual Behavior
·                     Sleep
·                     Sociability
·                     Thermoregulation
·                     Vasoconstriction
Selective (for 5-HT1A over other 5-HT receptors)
·                     F-15,599 (research compound, highly potent and selective for 5-HT1A)
·                     Flesinoxan (potent, EC50 = 24 nM)
·                     Gepirone (partial agonist, Ki = 70 nM)
·                     Haloperidol
·                     Ipsapirone (partial agonist, Ki = 12.1 nM)
·                     Quetiapine
·                     Trazodone (SARI, selective in the sense that on all other 5-HT receptors it acts as either an antagonist or has no action. Kd = 78nM)
·                     Yohimbine (unselective partial agonist)
·                     Tandospirone (potent and selective partial agonist)
Nonselective
·                     5-CT (potent - Ki = 250±50 pM)
·                     8-OH-DPAT (potent)
·                     Aripiprazole (atypical antipsychotic)
·                     Asenapine (atypical antipsychotic)
·                     Buspirone (partial agonist)
·                     Vortioxetine (high-efficacy partial agonist)
·                     Ziprasidone (Partial agonist, Ki = 3.4 nM)
·                     BMY 7378
·                     Cyanopindolol
·                     Iodocyanopindolol
·                     Lecozotan
·                     Methiothepin
·                     Methysergide
·                     NAN-190
·                     Nebivolol
·                     Nefazodone
·                     WAY-100,135
·                     WAY-100,635
·                     Mefway
·                     Analgesics (agonists)
·                     Antidepressants (post-synaptic receptor agonists and pre-synaptic autoreceptor antagonists serve as antidepressants)
·                     Anxiolytics (antagonist)
5-HT1B
(1992)
·                     HTR1B
·                     Blood Vessels
·                     CNS
·                     Addiction
·                     Aggression
·                     Anxiety
·                     Autoreceptor
·                     Learning
·                     Locomotion
·                     Memory
·                     Mood
·                     Penile Erection
·                     Sexual Behavior
·                     Vasoconstriction
·                     5-CT
·                     CGS-12066A
·                     CP-93,129
·                     CP-94,253
·                     Dihydroergotamine
·                     Eltoprazine
·                     Ergotamine
·                     Methysergide
·                     RU 24969
·                     TFMPP
·                     Triptans (antimigraine)
o        Zolmitriptan
o        Eletriptan
o        Sumatriptan
·                     Vortioxetine (partial agonist, Ki = 33 nM)
·                     Alprenolol
·                     AR-A000002
·                     Asenapine
·                     Cyanopindolol
·                     GR-127,935
·                     Iodocyanopindolol
·                     Isamoltane
·                     Metergoline
·                     Methiothepin
·                     Oxprenolol
·                     Pindolol
·                     Propranolol
·                     SB-216,641
·                     Yohimbine
·                     Migraines (e.g. triptans)
5-HT1D
(1991)
·                     HTR1D
·                     Blood Vessels
·                     CNS
·                     Anxiety
·                     Autoreceptor
·                     Locomotion
·                     Vasoconstriction
·                     5-CT
·                     CP-135,807
·                     Dihydroergotamine
·                     Ergotamine
·                     Methysergide
·                     Triptans (antimigraine)
o        Almotriptan
o        Eletriptan
o        Frovatriptan
o        Naratriptan
o        Rizatriptan
o        Sumatriptan
o        Zolmitriptan
·                     Yohimbine
·                     BRL-15572
·                     GR-127,935
·                     Ketanserin
·                     Metergoline
·                     Methiothepin
·                     Rauwolscine
·                     Ritanserin
·                     Vortioxetine (Ki = 54 nM)
·                     Ziprasidone
·                     Migraines (e.g. triptans)
5-HT1E
(1992)
·                     HTR1E
·                     Blood Vessels
·                     CNS
·                     BRL-54443
·                     None known
5-HT1F
(1993)
·                     HTR1F
·                     CNS
·                     Migraine
·                     BRL-54443
·                     Lasmiditan
·                     LY-334,370
·                     Naratriptan
·                     None known
5-HT2A
(1988)
·                     HTR2A
·                     Blood Vessels
·                     CNS
·                     GI Tract
·                     Platelets
·                     PNS
·                     Smooth Muscle
·                     Addiction (potentially modulating)
·                     Anxiety
·                     Appetite
·                     Cognition
·                     Imagination
·                     Learning
·                     Memory
·                     Mood
·                     Perception
·                     Sexual Behavior
·                     Sleep
·                     Thermoregulation
·                     Vasoconstriction
·                     25I-NBOMe (Full agonist)
·                     2C-B
·                     5-MeO-DMT
·                     BZP
·                     Bufotenin
·                     DMT
·                     DOM
·                     Ergonovine
·                     Lisuride
·                     LSD
·                     Mescaline
·                     Myristicin
·                     PNU-22394 (Partial agonist)
·                     Psilocin
·                     Psilocybin
·                     TFMPP (partial agonist or antagonist)
·                     Atypical antipsychotics
o        Clozapine
o        Olanzapine
o        Quetiapine
o        Risperidone
o        Ziprasidone
·                     Aripiprazole
·                     Asenapine
·                     Amitriptyline
·                     Clomipramine
·                     Cyproheptadine
·                     Eplivanserin
·                     Etoperidone
·                     Haloperidol
·                     Hydroxyzine
·                     Iloperidone
·                     Ketanserin (antihypertensive)
·                     Methysergide
·                     Mianserin
·                     Mirtazapine
·                     Nefazodone
·                     Pimavanserin
·                     Pizotifen
·                     Ritanserin
·                     Trazodone
·                     Yohimbine
·                     Atypical antipsychotics (antagonist)
·                     Psychedelics (partial agonists)
·                     NaSSAs (antidepressants and anxiolytics; they serve as antagonists at this site)
·                     Treating serotonin syndrome (antagonists; e.g. cyproheptadine)
·                     Sleeping aid (antagonists; e.g. trazodone)
5-HT2B
(1992)
·                     HTR2B
·                     Blood Vessels
·                     CNS
·                     GI Tract
·                     Platelets
·                     PNS
·                     Smooth Muscle
·                     Anxiety
·                     Appetite
·                     Cardiovascular Function
·                     GI Motility
·                     Sleep
·                     Vasoconstriction
·                     BW-723C86
·                     Fenfluramine
·                     MDMA
·                     Norfenfluramine
·                     PNU-22394 (Partial agonist)
·                     Ro60-0175
·                     Agomelatine
·                     Asenapine
·                     BZP
·                     Ketanserin
·                     Methysergide
·                     Ritanserin
·                     RS-127,445
·                     Tegaserod
·                     Yohimbine
·                     Migraines (antagonists)
5-HT2C
(1988)
·                     HTR2C
·                     Blood Vessels
·                     CNS
·                     GI Tract
·                     Platelets
·                     PNS
·                     Smooth Muscle
·                     Addiction. (potentially modulating)
·                     Anxiety
·                     Appetite
·                     GI Motility
·                     Heteroreceptor for norepinephrine and dopamine
·                     Locomotion
·                     Mood
·                     Penile Erection
·                     Sexual Behavior
·                     Sleep
·                     Thermoregulation
·                     Vasoconstriction
·                     A-372,159
·                     AL-38022A
·                     Aripiprazole
·                     Ergonovine
·                     Lorcaserin
·                     PNU-22394 (Full agonist)
·                     Ro60-0175
·                     TFMPP
·                     Trazodone (hypnotic)
·                     YM-348
·                     Agomelatine (antidepressant)
·                     Amitriptyline
·                     Asenapine
·                     Clomipramine
·                     Clozapine (antipsychotic)
·                     Cyproheptadine
·                     Dimebolin
·                     Eltoprazine
·                     Etoperidone
·                     Fluoxetine
·                     Haloperidol
·                     Iloperidone
·                     Ketanserin (antihypertensive)
·                     Lisuride
·                     Methysergide
·                     Mianserin
·                     Mirtazapine
·                     Nefazodone
·                     Olanzapine
·                     Paroxetine
·                     Quetiapine
·                     Risperidone
·                     Ritanserin
·                     Tramadol
·                     Trazodone
·                     Ziprasidone
·                     Antidepressant (e.g. agomelatine, fluoxetine, mirtazapine)
·                     Orexigenic (e.g. mirtazapine, clozapine and olanzapine; antagonists)
·                     Anorectic (Lorcaserin)
·                     Antipsychotic (Vabicaserin; agonists)
5-HT3
(1993)
·                     HTR3A
·                     HTR3B
·                     HTR3C
·                     HTR3D
·                     HTR3E
·                     CNS
·                     GI Tract
·                     PNS
·                     Addiction
·                     Anxiety
·                     Emesis
·                     GI Motility
·                     Learning
·                     Memory
·                     Nausea
·                     2-Methyl-5-HT
·                     BZP
·                     Quipazine
·                     RS-56812
·                     Alosetron
·                     Several antiemetics
o        Dolasetron
o        Ondansetron
o        Granisetron
o        Tropisetron
·                     Clozapine
·                     Memantine
·                     Metoclopramide
·                     Mianserin
·                     Mirtazapine
·                     Olanzapine
·                     Quetiapine
·                     Vortioxetine (Ki = 3.7 nM)
·                     Antiemetic
5-HT4
(1995)
·                     HTR4
·                     CNS
·                     GI Tract
·                     PNS
·                     Anxiety
·                     Appetite
·                     GI Motility
·                     Learning
·                     Memory
·                     Mood
·                     Respiration
·                     5-MT
·                     BIMU-8
·                     Cinitapride
·                     Cisapride (gastroprokinetic)
·                     Dazopride
·                     Metoclopramide
·                     Mosapride
·                     Prucalopride
·                     RS-67333
·                     Renzapride
·                     Tegaserod
·                     Zacopride
·                     L-Lysine
·                     Piboserod
·                     Gastroprokinetics (e.g. Tegaserod)
5-HT5A
(1994)
·                     HTR5A
·                     CNS
·                     Autoreceptor
·                     Locomotion[81]
·                     Sleep
·                     5-CT
·                     Ergotamine
·                     Valerenic Acid (partial agonist)
·                     Asenapine
·                     Dimebolin
·                     Methiothepin
·                     Ritanserin
·                     SB-699,551
·                     SB-699,551-A
·                     None thus far
5-HT5B
(1993)
·                     HTR5BP
·                     functions in rodents,
pseudogene in humans
·                     None thus far
5-HT6
(1993)
·                     HTR6
·                     CNS
·                     Anxiety
·                     Cognition
·                     Learning
·                     Memory
·                     Mood
·                     EMD-386,088
·                     EMDT
·                     Amitriptyline
·                     Aripiprazole
·                     Asenapine
·                     Clomipramine
·                     Clozapine
·                     Dimebolin
·                     EGIS-12233
·                     Haloperidol
·                     Iloperidone
·                     MS-245
·                     Olanzapine
·                     Ro04-6790
·                     SB-258,585
·                     SB-271,046
·                     SB-357,134
·                     SB-399,885
·                     Antidepressant (antagonists and agonists)
·                     Anxiolytic (antagonists and agonist)
·                     Nootropic (antagonists)
·                     Anorectic (antagonists)
5-HT7
(1993)
·                     HTR7
·                     Blood Vessels
·                     CNS
·                     GI Tract
·                     Anxiety
·                     Autoreceptor
·                     Memory
·                     Mood
·                     Respiration
·                     Sleep
·                     Thermoregulation
·                     Vasoconstriction
·                     5-CT
·                     8-OH-DPAT
·                     Aripiprazole (weak partial agonist)
·                     AS-19
·                     E-55888
·                     RA-7
·                     Amitriptyline
·                     Asenapine
·                     Clomipramine
·                     Clozapine
·                     EGIS-12233
·                     Haloperidol
·                     Iloperidone
·                     Imipramine
·                     Ketanserin
·                     Mirtazapine
·                     Olanzapine
·                     Ritanserin
·                     Risperidone
·                     SB-269,970
·                     Vortioxetine (Ki = 19 nM)
·                     Antidepressant (antagonists)
·                     Anxiolytics (antagonists)
·                     Nootropic (antagonists)
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.
Very nonselective agonists of 5-HT receptor subtypes include ergotamine (an antimigraine), which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. LSD (a psychedelic) is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist.
5-HT4 receptor
[5-hydroxytryptamine (serotonin) receptor 4, G protein-coupled]
            5-Hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.
            This gene is a member of the family of human serotonin receptors, which are G protein-coupled receptors that stimulate cAMP production in response to serotonin (5-hydroxytryptamine). The gene product is a glycosylated transmembrane protein that functions in both the peripheral and central nervous system to modulate the release of various neurotransmitters. Multiple transcript variants encoding proteins with distinct C-terminal sequences have been described, but the full-length nature of some transcript variants has not been determined.
Location
            The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system (CNS). In the CNS the receptor appears in the putamen, caudate nucleus, nucleus accumbens, globus pallidus, and substantia nigra, and to a lesser extent in the neocortex, raphe, pontine nuclei, and some areas of the thalamus. It has not been found in the cerebellum.
Isoforms
            Internalization is isoform-specific.
Ligands
            Several drugs that act as 5-HT4 selective agonists have recently been introduced into use in both scientific research and clinical medicine. Some drugs that act as 5-HT4 agonists are also active as 5-HT3 antagonists, such as mosapride, metoclopramide, renzapride, and zacopride, and so these compounds cannot be considered highly selective. Research in this area is ongoing.
            SB-207,145 radiolabeled with carbon-11 is used as a radioligand for 5-HT4 in positron emission tomography pig and human studies.
Agonists
  • BIMU-8
  • Cisapride
  • CJ-033,466 - partial agonist
  • ML-10302
  • Mosapride
  • Prucalopride
  • Renzapride
  • RS-67506
  • RS-67333 - partial agonist
  • SL65.0155 - partial agonist
  • Tegaserod
  • Zacopride
  • Metoclopramide
  • Sulpiride
Antagonists
  • Piboserod
  • GR-113,808 (1-methyl-1H-indole-3-carboxylic acid, [1-[2-[(methylsulfonyl) amino] ethyl] -4-piperidinyl]methyl ester)
  • GR-125,487
  • RS-39604 (1-[4-Amino-5-chloro-2-(3,5-dimethoxyphenyl)methyloxy]-3-[1-[2-methyl sulphonylamino]piperidin-4-yl]propan-1-one)
  • SB-203,186
  • SB-204,070
  • ([Methoxy-11C]1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate
  • Chamomile (ethanol extract)


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