Tag: 5-HT Receptor

What is Naphthylpiperainze?

Published on by Andrew Marshall2 Comments

Introduction

1-(1-Naphthyl)piperazine (1-NP) is a drug which is a phenylpiperazine derivative.

It acts as a non-selective, mixed serotonergic agent, exerting partial agonism at the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptors, while antagonising the 5-HT2A, 5-HT2B, and 5-HT2C receptors. It has also been shown to possess high affinity for the 5-HT3, 5-HT5A, 5-HT6, and 5-HT7 receptors, and may bind to 5-HT4 and the SERT as well. In animals it produces effects including hyperphagia, hyperactivity, and anxiolysis, of which are all likely mediated predominantly or fully by blockade of the 5-HT2C receptor.

What is Fluprazine?

Published on by Andrew Marshall2 Comments

Introduction

Fluprazine (DU-27,716) is a drug of the phenylpiperazine class.

It is a so-called serenic or antiaggressive agent.

It is closely related to several other piperazines, including eltoprazine and batoprazine, and TFMPP, as well as more distantly to the azapirones such as buspirone.

The pharmacology of fluprazine is unknown, but it is likely to act as an agonist at the 5-HT1A and 5-HT1B receptors like its sister compound eltoprazine.

What is Eltoprazine?

Published on by Andrew Marshall3 Comments

Introduction

Eltoprazine (developmental code name DU-28,853) is a serotonergic drug of the phenylpiperazine class which is described as a serenic, or anti-aggressive agent.

It acts as an agonist of the serotonin 5-HT1A and 5-HT1B receptors and as an antagonist of the serotonin 5-HT2C receptor. The drug is closely related to batoprazine, fluprazine and batoprazine, which are similarly acting agents, and is also a known chemical precursor to S-15535 and lecozotan.

Eltoprazine is or was under development for the treatment of aggression, attention deficit hyperactivity disorder (ADHD), cognitive disorders, and drug-induced dyskinesia, but no recent development has been reported for these indications as of February 2022. It was also under development for the treatment of psychotic disorders, but development for this indication was discontinued.

Eltoprazine was originated by Solvay and was developed by Elto Pharma, PsychoGenics, and Solvay.

What is a Serotonin Receptor Agonist?

Published on by Andrew MarshallLeave a comment

Introduction

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

Non-Selective Agonists

Serotonergic psychedelics such as tryptamines (e.g. psilocybin, psilocin, DMTTooltip dimethyltryptamine, 5-MeO-DMT, bufotenin), lysergamides (e.g. LSDTooltip lysergic acid diethylamide, ergine (LSA)), phenethylamines (e.g. mescaline, 2C-B, 25I-NBOMe), and amphetamines (e.g. MDATooltip 3,4-methylenedioxyamphetamine, DOMTooltip 2,5-dimethoxy-4-methylamphetamine) are non-selective agonists of serotonin receptors. Their hallucinogenic effects are specifically mediated by activation of the 5-HT2A receptor.

Drugs that increase extracellular serotonin levels such as serotonin reuptake inhibitors (e.g. fluoxetine, venlafaxine), serotonin releasing agents (e.g. fenfluramine, MDMATooltip methylenedioxymethamphetamine), and monoamine oxidase inhibitors (e.g. phenelzine, moclobemide) are indirect non-selective serotonin receptor agonists. They are used variously as antidepressants, anxiolytics, antiobsessionals, appetite suppressants, and entactogens.

5-HT1 Receptor agonists

5-HT1A Receptor Agonists

Azapirones such as buspirone, gepirone, and tandospirone are 5-HT1A receptor partial agonists marketed primarily as anxiolytics, but also as antidepressants. The antidepressants vilazodone and vortioxetine are 5-HT1A receptor partial agonists. Flibanserin, a drug used for female sexual dysfunction, is a 5-HT1A receptor partial agonist. Many atypical antipsychotics, such as aripiprazole, asenapine, clozapine, lurasidone, quetiapine, and ziprasidone, are 5-HT1A receptor partial agonists, and this action is thought to contribute to their beneficial effects on negative symptoms in schizophrenia.

5-HT1B Receptor Agonists

Triptans such as sumatriptan, rizatriptan, and naratriptan are 5-HT1B receptor agonists that are used to abort migraine and cluster headache attacks. The ergoline antimigraine agent ergotamine also acts on this receptor.

Serenics such as batoprazine, eltoprazine, and fluprazine are agonists of the 5-HT1B receptor and other serotonin receptors, and have been found to produce anti-aggressive effects in animals, but have not been marketed. Eltoprazine is under development for the treatment of aggression and for other indications.

5-HT1D Receptor Agonists

In addition to being 5-HT1B agonists, triptans (i.e. sumatriptan, almotriptan, zolmitriptan, naratriptan, eletriptan, frovatriptan and rizatriptan) are also agonists at the 5-HT1D receptor, which contributes to their antimigraine effect caused by vasoconstriction of blood vessels in the brain. The same is true for ergotamine.

5-HT1E Receptor Agonists

The triptan eletriptan is an agonist of the 5-HT1E receptor. BRL-54443 is a selective 5-HT1E and 5-HT1F receptor agonist which is used in scientific research.

5-HT1F Receptor Agonists

Triptans such as eletriptan, naratriptan, and sumatriptan are agonists of the 5-HT1F receptor. Lasmiditan is a selective 5-HT1F agonist that is under development by Eli Lilly and Company for the treatment of migraine.

5-HT2 Receptor Agonists

5-HT2A Receptor Agonists

Serotonergic psychedelics like psilocybin, LSD, and mescaline act as 5-HT2A receptor agonists. Their actions at this receptor are thought to be responsible for their hallucinogenic effects. Most of these drugs also act as agonists of other serotonin receptors. Not all 5-HT2A receptor agonists are psychoactive.

The 25-NB (NBOMe) series is a family of phenethylamine serotonergic psychedelics that, unlike other classes of serotonergic psychedelics, act as highly selective 5-HT2A receptor agonists. The most well-known member of the 25-NB series is 25I-NBOMe. (2S,6S)-DMBMPP is an analogue of the 25-NB compounds and is the most highly selective agonist of the 5-HT2A receptor that has been identified to date. O-4310 (1-isopropyl-6-fluoropsilocin) is a tryptamine derivative that is a highly selective agonist of the 5-HT2A receptor.

Selective 5-HT2A receptor agonists like the 25-NB compounds, specifically those which can behave as full agonists at this receptor, can cause serotonin syndrome-like adverse effects such as hyperthermia, hyperpyrexia, tachycardia, hypertension, clonus, seizures, agitation, aggression, and hallucinations which has ended in death on numerous occasions despite these particular drugs only being available to drug users for about 2–3 years, being widely in use mostly in the period from 2010-2012. Bans were put in place around 2012-2013 by countries where they had risen to popularity. They quickly and often accidentally lead to overdose. In contrast to the aforementioned drugs’s potent, selective, and most importantly, full agonism (meaning the drug can fully activate the receptor to 100% of its activation potential, and does so even with minuscule amounts due to high potency, LSD, like the other “safe” psychedelics which are almost impossible to overdose fatally on, is a partial agonist, and this means it has a limit of how much it can activate the receptor, a limit which is basically impossible to exceed even with exponentially larger amounts of the drug. These partial agonists have proven relatively safe after having seen widespread abuse by drug users for many decades. Activation of the 5-HT2A receptor is also implicated in serotonin syndrome caused by indirect serotonin receptor agonists like serotonin reuptake inhibitors, serotonin releasing agents, and monoamine oxidase inhibitors. Antagonists of the 5-HT2A receptor like cyproheptadine and chlorpromazine are able to reverse and mediate recovery from serotonin syndrome.

5-HT2B Receptor Agonists

Agonists of the 5-HT2B receptor are implicated in the development of cardiac fibrosis. Fenfluramine, pergolide, and cabergoline have been withdrawn from some markets for this reason. Many serotonergic psychedelics, such as LSD and psilocin, have been shown to activate this receptor directly. MDMA has been reported to be both a potent direct agonist and have an indirect effect by increasing plasma serotonin levels.

5-HT2C Receptor Agonists

Lorcaserin is an appetite suppressant and anti-obesity drug which acts as a selective 5-HT2C receptor agonist. meta-Chlorophenylpiperazine (mCPP) is a 5-HT2C-preferring serotonin receptor agonist that induces anxiety and depression and can cause panic attacks in susceptible individuals.

5-HT3 Receptor Agonists

2-Methyl-5-hydroxytryptamine (2-methylserotonin) and quipazine are moderately selective agonists of the 5-HT3 receptor that are used in scientific research. Agonists of this receptor are known to induce nausea and vomiting, and are not used medically.

5-HT4 Receptor Agonists

Cisapride and tegaserod are 5-HT4 receptor partial agonists that were used to treat disorders of gastrointestinal motility. Prucalopride is a highly selective 5-HT4 receptor agonist that can be used to treat certain disorders of gastrointestinal motility. Other 5-HT4 receptor agonists have shown potential to be nootropic and antidepressant drugs, but have not been marketed for such indications.

5-HT5A Receptor Agonists

Valerenic acid, a constituent of valerian root, has been found to act as a 5-HT5A receptor agonist, and this action could be involved in the sleep-promoting effects of valerian.

5-HT6 Receptor Agonists

No selective agonists of the 5-HT6 receptor have been approved for medical use. Selective 5-HT6 receptor agonists like E-6801, E-6837, EMDT, WAY-181,187, and WAY-208,466 show antidepressant, anxiolytic, anti-obsessional, and appetite suppressant effects in animals, but also impair cognition and memory.

5-HT7 Receptor Agonists

AS-19 is a 5-HT7 receptor agonist that has been used in scientific research.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Serotonin_receptor_agonist >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of the 5-HT7 Receptor

Published on by Andrew Marshall9 Comments

Introduction

The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The 5-HT7 receptor is coupled to Gs (stimulates the production of the intracellular signalling molecule cAMP) and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels. This receptor has been a drug development target for the treatment of several clinical disorders. The 5-HT7 receptor is encoded by the HTR7 gene, which in humans is transcribed into 3 different splice variants.

Function

When the 5-HT7 receptor is activated by serotonin, it sets off a cascade of events starting with release of the stimulatory G protein Gs from the GPCR complex. Gs in turn activates adenylate cyclase which increases intracellular levels of the second messenger cAMP.

The 5-HT7 receptor plays a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract. The highest 5-HT7 receptor densities are in the thalamus and hypothalamus, and it is present at higher densities also in the hippocampus and cortex. The 5-HT7 receptor is involved in thermoregulation, circadian rhythm, learning and memory, and sleep. Peripheral 5-HT7 receptors are localised in enteric nerves; high levels of 5-HT7 receptor-expressing mucosal nerve fibres were observed in the colon of patients with irritable bowel syndrome. An essential role of 5-HT7 receptor in intestinal hyperalgesia was demonstrated in mouse models with visceral hypersensitivity, of which a novel 5-HT7 receptor antagonist administered perorally reduced intestinal pain levels. It is also speculated that this receptor may be involved in mood regulation, suggesting that it may be a useful target in the treatment of depression.

Variants

Three splice variants have been identified in humans (designated h5-HT7(a), h5-HT7(b), and h5-HT7(d)), which encode receptors that differ in their carboxy terminals. The h5-HT7(a) is the full length receptor (445 amino acids), while the h5-HT7(b) is truncated at amino acid 432 due to alternative splice donor site. The h5-HT7(d) is a distinct isoform of the receptor: the retention of an exon cassette in the region encoding the carboxyl terminal results a 479-amino acid receptor with a c-terminus markedly different from the h5-HT7(a). A 5-HT7(c) splice variant is detectable in rat tissue but is not expressed in humans. Conversely, rats do not express a splice variant homologous to the h5-HT7(d), as the rat 5-HT7 gene lacks the exon necessary to encode this isoform. Drug binding affinities are similar across the three human splice variants; however, inverse agonist efficacies appear to differ between the splice variants.

Discovery

In 1983, evidence for a 5-HT1-like receptor was first found. Ten years later, 5-HT7 receptor was cloned and characterised. It has since become clear that the receptor described in 1983 is 5-HT7.

Ligands

Numerous orthosteric ligands of moderate to high affinity are known. Signalling biased ligands were discovered and developed in 2018.

Agonists

Agonists mimic the effects of the endogenous ligand, which is serotonin at the 5-HT7 receptor (↑cAMP).

  • 5-Carboxamidotryptamine (5-CT)
  • 5-methoxytryptamine (5-MT, 5-MeOT)
  • 8-OH-DPAT (mixed 5-HT1A/5-HT7 agonist)
  • Aripiprazole (weak partial agonist)
  • AS-19
  • E-55888
  • E-57431
  • LP-12 (4-(2-Diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide)
  • LP-44 (4-[2-(Methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide)
  • LP-211
  • MSD-5a
  • Nω-Methylserotonin
  • N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides (can function as either an agonist or antagonist depending on side chain substitution)
  • N,N-Dimethyltryptamine
  • AGH-107 (water-soluble, brain penetrating full agonist)
  • AH-494 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide)
  • AGH-192 (orally bioavailable, water-soluble, brain penetrating full agonist)

Antagonists

Neutral antagonists (also known as silent antagonists) bind the receptor and have no intrinsic activity but will block the activity of agonists or inverse agonists. Inverse agonists inhibit the constitutive activity of the receptor, producing functional effects opposite to those of agonists (at the 5-HT7 receptor: ↓cAMP). Neutral antagonists and inverse agonists are typically referred to collectively as “antagonists” and, in the case of the 5-HT7 receptor, differentiation between neutral antagonists and inverse agonists is problematic due to differing levels of inverse agonist efficacy between receptor splice variants. For instance, mesulergine and metergoline are reported to be neutral antagonists at the h5-HT7(a) and h5-HT7(d) receptor isoforms but these drugs display marked inverse agonist effects at the h5-HT7(b) splice variant.

  • 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one
  • Amisulpride
  • Amitriptyline
  • Amoxapine
  • Brexpiprazole
  • Clomipramine
  • Clozapine
  • CYY1005 (a highly selective, orally active 5-HT7 antagonist)
  • DR-4485
  • EGIS-12233 (mixed 5-HT6/5-HT7 antagonist)
  • AVN-101 (mixed 5-HT6/5-HT7 antagonist)
  • Fluphenazine
  • Fluperlapine
  • ICI 169,369
  • Imipramine
  • JNJ-18038683
  • Ketanserin
  • Loxapine
  • Lurasidone
  • LY-215,840
  • Maprotiline
  • Mesulergine
  • Methysergide
  • Mianserin
  • Olanzapine
  • Pimozide
  • RA-7 (1-(2-diphenyl)piperazine)
  • Ritanserin
  • SB-258,719
  • SB-258741
  • SB-269970 (highly 5-HT7 selective)
  • SB-656104-A
  • SB-691673
  • Sertindole
  • Spiperone
  • Tenilapine
  • TFMPP
  • Vortioxetine
  • Trifluoperazine
  • Ziprasidone
  • Zotepine

Inactivating Antagonists

Inactivating antagonists are non-competitive antagonists that render the receptor persistently insensitive to agonist, which resembles receptor desensitisation. Inactivation of the 5-HT7 receptor, however, does not arise from the classically described mechanisms of receptor desensitisation via receptor phosphorylation, beta-arrestin recruitment, and receptor internalization. Inactivating antagonists all likely interact with the 5-HT7 receptor in an irreversible/pseudo-irreversible manner, as is the case with risperidone.

  • Bromocriptine
  • Lisuride
  • Metergoline
  • Methiothepin
  • Paliperidone
  • Risperidone

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/5-HT7_receptor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of the 5-HT6 Receptor

Published on by Andrew Marshall7 Comments

Introduction

The 5HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.

Distribution

The 5HT6 receptor is expressed almost exclusively in the brain. It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex (frontal and entorhinal regions), nucleus accumbens, striatum, caudate nucleus, hippocampus, and the molecular layer of the cerebellum. Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5-HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.

Function

Blockade of central 5-HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas, whereas activation enhances GABAergic signaling in a widespread manner. Antagonism of 5-HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex, while stimulation has the opposite effect.

As a Drug Target for Antagonists

Despite the 5HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity. In parallel with this, 5-HT6 antagonists are hypothesized to improve cognition, learning, and memory. Agents such as latrepirdine, idalopirdine (Lu AE58054), and intepirdine (SB-742,457/RVT-101) were evaluated as novel treatments for Alzheimer’s disease and other forms of dementia. However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.

5HT6 antagonists have also been shown to reduce appetite and produce weight loss, and as a result, PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.

As a Drug Target for Agonists

Recently, the 5-HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions. Additionally, indirect 5HT6 activation may play a role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

Ligands

A large number of selective 5HT6 ligands have now been developed.

Agonists

  • Full Agonists:
    • 2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT)
    • WAY-181,187
    • WAY-208,466
    • N-(inden-5-yl)imidazothiazole-5-sulfonamide (43): Ki = 4.5nM, EC50 = 0.9nM, Emax = 98%
    • E-6837 – Full agonist at human 5-HT6 receptors
  • Partial Agonists:
    • E-6801
    • E-6837 – partial agonist at rat 5-HT6 receptors. Orally active in rats, and caused weight loss with chronic administration
    • EMD-386,088 – potent partial agonist (EC50 = 1 nM) but non-selective
    • LSD – Emax = 60%

Antagonists and Inverse Agonists

  • ALX-1161
  • AVN-211
  • BVT-5182
  • BVT-74316
  • Cerlapirdine – selective
  • EGIS-12233 – mixed 5-HT6 / 5-HT7 antagonist
  • Idalopirdine (Lu AE58054) – selective
  • Intepirdine (SB-742,457/RVT-101) – selective antagonist
  • Landipirdine (RO-5025181, SYN-120)
  • Latrepirdine and analogues
  • MS-245
  • PRX-07034
  • SB-258,585
  • SB-271,046
  • SB-357,134
  • SB-399,885
  • SGS 518 Fb: [445441-26-9]
  • Ro 04-6790
  • Ro-4368554
  • Atypical antipsychotics (sertindole, olanzapine, asenapine, clozapine)
  • WAY-255315 / SAM-315: Ki = 1.1 nM, IC50 = 13 nM
  • Rosa rugosa extract

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/5-HT6_receptor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of the 5-HT5A Receptor

Published on by Andrew Marshall4 Comments

Introduction

5-Hydroxytryptamine (serotonin) receptor 5A, also known as HTR5A, is a protein that in humans is encoded by the HTR5A gene. Agonists and antagonists for 5-HT receptors, as well as serotonin uptake inhibitors, present promnesic (memory-promoting) and/or anti-amnesic effects under different conditions, and 5-HT receptors are also associated with neural changes.

Function

The gene described in this record is a member of 5-hydroxytryptamine receptor family and encodes a multi-pass membrane protein that functions as a receptor for 5-hydroxytryptamine and couples to G proteins, negatively influencing cAMP levels via Gi and Go. This protein has been shown to function in part through the regulation of intracellular Ca2+ mobilisation. The 5-HT5A receptor has been shown to be functional in a native expression system.

Rodents have been shown to possess two functional 5-HT5 receptor subtypes, 5-HT5A and 5-HT5B, however while humans possess a gene coding for the 5-HT5B subtype, its coding sequence is interrupted by stop codons, making the gene non-functional, and so only the 5-HT5A subtype is expressed in human brain.

It also appears to serve as a presynaptic serotonin autoreceptor.

Clinical Significance

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in a wide range of psychiatric conditions and also has vasoconstrictive and vasodilatory effects.

Selective Ligands

Few highly selective ligands are commercially available for the 5-HT5A receptor. When selective activation of this receptor is desired in scientific research, the non-selective serotonin receptor agonist 5-Carboxamidotryptamine can be used in conjunction with selective antagonists for its other targets (principally 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT7). Research in this area is ongoing.

Agonists

  • LSD:(+)-lysergic acid
  • Lisuride, partial agonist
  • 5-CT, full agonist
  • Methylergometrine, full agonist
  • Valerenic acid, a component of valerian, has been shown to act as a 5HT5A partial agonist
  • Olanzapine, an atypical antipsychotic
  • Psilocin
  • Another ligand that has been recently disclosed is shown below, claimed be a selective 5-HT5A agonist with Ki = 124 nM

Antagonists

  • ASP-5736
  • AS-2030680
  • AS-2674723
  • MS112, selective potent antangonist
  • Latrepirdine (non-selective)
  • Risperidone (non-selective), moderate 206 nM affinity.
  • SB-699,551

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/5-HT5A_receptor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of the 5-HT4 Receptor

Published on by Andrew Marshall4 Comments

Introduction

5-Hydroxytryptamine receptor 4 (5-HT4 receptor) is a protein that in humans is encoded by the HTR4 gene.

Refer to 5-HT receptor.

Function

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

Internalisation 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. Amongst these agonists prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors.

SB-207,145 radiolabelled with carbon-11 is used as a radioligand for 5-HT4 in positron emission tomography pig and human studies.

Agonists

  • Tropisetron – partial agonist
  • 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
  • Naronapride

Antagonists

  • l-lysine
  • 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-methylsulphonylamino]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)

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/5-HT4_receptor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of the 5-HT3 Receptor

Published on by Andrew Marshall10 Comments

Introduction

The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs) and therefore differs structurally and functionally from all other 5-HT receptors (5-hydroxytryptamine, or serotonin receptors) which are G protein-coupled receptors. This ion channel is cation-selective and mediates neuronal depolarisation and excitation within the central and peripheral nervous systems.

As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to sodium (Na), potassium (K), and calcium (Ca) ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The rapidly activating, desensitising, inward current is predominantly carried by sodium and potassium ions. 5-HT3 receptors have a negligible permeability to anions. They are most closely related by homology to the nicotinic acetylcholine receptor.

Brief History

Identification of the 5-HT3 receptor did not take place until 1986, lacking selective pharmacological tools. However, with the discovery that the 5-HT3 receptor plays a prominent role in chemotherapy- and radiotherapy-induced vomiting, and the concomitant development of selective 5-HT3 receptor antagonists to suppress these side effects aroused intense interest from the pharmaceutical industry and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.

Structure

The 5-HT3 receptor differs markedly in structure and mechanism from the other 5-HT receptor subtypes, which are all G-protein-coupled. A functional channel may be composed of five identical 5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B, 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric). It appears that only the 5-HT3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerise with 5-HT3A subunits to form functional channels. Additionally, there has not currently been any pharmacological difference found between the heteromeric 5-HT3AC, 5-HT3AD, 5-HT3AE, and the homomeric 5-HT3A receptor. N-terminal glycosylation of receptor subunits is critical for subunit assembly and plasma membrane trafficking.

The subunits surround a central ion channel in a pseudo-symmetric manner. Each subunit comprises an extracellular N-terminal domain which comprises the orthosteric ligand-binding site; a transmembrane domain consisting of four interconnected alpha helices (M1-M4), with the extracellular M2-M3 loop involved in the gating mechanism; a large cytoplasmic domain between M3 and M4 involved in receptor trafficking and regulation; and a short extracellular C-terminus. Whereas extracellular domain is the site of action of agonists and competitive antagonists, the transmembrane domain contains the central ion pore, receptor gate, and principle selectivity filter that allows ions to cross the cell membrane.

Human and Mouse Genes

The genes encoding human 5-HT3 receptors are located on chromosomes 11 (HTR3A, HTR3B) and 3 (HTR3C, HTR3D, HTR3E), so it appears that they have arisen from gene duplications. The genes HTR3A and HTR3B encode the 5-HT3A and 5-HT3B subunits and HTR3C, HTR3D and HTR3E encode the 5-HT3C, 5-HT3D and 5-HT3E subunits. HTR3C and HTR3E do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased 5-HT efficacies. The pathophysiological role for these additional subunits has yet to be identified.

The human 5-HT3A receptor gene is similar in structure to the mouse gene which has 9 exons and is spread over ~13 kb. Four of its introns are exactly in the same position as the introns in the homologous α7-acetylcholine receptor gene, clearly showing their evolutionary relationship.

  • Expression: The 5-HT3C, 5-HT3D and 5-HT3E genes tend to show peripherally restricted pattern of expression, with high levels in the gut. In human duodenum and stomach, for example, 5-HT3C and 5-HT3E mRNA might be greater than for 5-HT3A and 5-HT3B.
  • Polymorphism: In patients treated with chemotherapeutic drugs, certain polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HTR3B receptor subunit could be used as biomarker of antiemetic drug efficacy.

Tissue Distribution

The 5-HT3 receptor is expressed throughout the central and peripheral nervous systems and mediates a variety of physiological functions. On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons, amygdala, and hippocampus, and in ferret visual cortex. 5-HT3 receptors are also present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release, but evidence is inconclusive.

Effects

When the receptor is activated to open the ion channel by agonists, the following effects are observed:

  • Central nervous system (CNS): nausea and vomiting centre in brain stem, anxiety, as well as anticonvulsant and pro-nociceptive activity.
  • Peripheral nervous system (PNS): neuronal excitation (in autonomic, nociceptive neurons), emesis.

Agonists

Agonists for the receptor include:

  • Cereulide
  • 2-methyl-5-HT
  • Alpha-Methyltryptamine
  • Bufotenin
  • Chlorophenylbiguanide
  • Ethanol
  • Ibogaine
  • Phenylbiguanide
  • Quipazine
  • RS-56812: Potent and selective 5-HT3 partial agonist, 1000x selectivity over other serotonin receptors
  • SR-57227
  • Varenicline
  • YM-31636
  • S 21007(SAR c.f. CGS-12066A)

Antagonists

Antagonists for the receptor (sorted by their respective therapeutic application) include:

  • Antiemetics
    • AS-8112
    • Granisetron
    • Ondansetron
    • Tropisetron
  • Gastroprokinetics
    • Alosetron
    • Batanopride
    • Metoclopramide (high doses)
    • Renzapride
    • Zacopride
    • M1, the major active metabolite of mosapride
  • Antidepressants
  • Antipsychotics
  • Antimalarials
    • Quinine
    • Chloroquine
    • Mefloquine
  • Others
    • 3-Tropanyl indole-3-carboxylate
    • Cannabidiol (CBD)
    • Delta-9-Tetrahydrocannabinol
    • Lamotrigine (epilepsy and bipolar disorder)
    • Memantine (Alzheimer’s disease medication)
    • Menthol
    • Thujone

Positive Allosteric Modulators

These agents are not agonists at the receptor, but increase the affinity or efficacy of the receptors for an agonist:

  • Indole Derivatives
  • 5-chloroindole
  • Small Organic Anaesthetics
  • Ethanol
  • Chloroform
  • Halothane
  • Isoflurane

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/5-HT3_receptor >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.