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5-HT3antagonist

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5-HT3receptor antagonist
Drug class
Skeletal formulaofondansetron,the prototypical 5-HT3antagonist
Class identifiers
UseNauseaandVomiting
ATC codeA04AA
Biological target5-HT3receptor
Clinical data
DrugsDrug Classes
Consumer ReportsBest Buy Drugs
External links
MeSHD058831
Legal status
In Wikidata

The5-HT3antagonists,informally known as "setrons",are aclass of drugsthat act asreceptor antagonistsat the5-HT3receptor,a subtype ofserotoninreceptorfound in terminals of thevagus nerveand in certain areas of the brain. With the notable exceptions ofalosetronandcilansetron,which are used in the treatment ofirritable bowel syndrome,all 5-HT3antagonists areantiemetics,used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced bycancer chemotherapyand are considered the gold standard for this purpose.[1]

The 5-HT3antagonists may be identified by the suffix-setron,[2]and are classified under codeA04AAof theWHO'sAnatomical Therapeutic Chemical Classification System.

Medical uses[edit]

5-HT3antagonists are most effective in the prevention and treatment ofchemotherapy-induced nausea and vomiting(CINV), especially that caused by highlyemetogenicdrugs such ascisplatin;when used for this purpose, they may be given alone or, more frequently, with aglucocorticoid,usuallydexamethasone.They are usually givenintravenously,shortly before administration of the chemotherapeutic agent,[3]although some authors have argued that oral administration may be preferred.[4] The concomitant administration of aNK1receptor antagonist,such asaprepitant,significantlyincreases the efficacy of 5-HT3antagonists in preventing both acute and delayed CINV.[5]

The 5-HT3antagonists are also indicated in the prevention and treatment ofradiation-inducednausea and vomiting (RINV), when needed, andpostoperative nausea and vomiting(PONV). Although they are more effective at controlling CINV—where they stop symptoms altogether in up to 70% of people, and reduce them in the remaining 30%—, they are just as effective as other agents for PONV.

Current evidence suggests that 5-HT3antagonists are ineffective in controllingmotion sickness.[6][7][8]Arandomized, placebo-controlled trialof ondansetron to treat motion sickness inair ambulancepersonnel showed subjective improvement, but it was notstatistically significant.[9]

Available agents[edit]

  • Ondansetronwas the first 5-HT3antagonist, developed byGlaxoaround 1984. Its efficacy was first established in 1987, in animal models,[10][11]and it was extensively studied over the following years.[12]Ondansetron was approved by the U.S.Food and Drug Administrationin 1991, and has since become available in several other countries, including the UK, Ireland, Australia, Canada, France and Brazil. As of 2008, ondansetron and granisetron are the only 5-HT3antagonists available as ageneric drugin the United States. Ondansetron may be given several times daily, depending on the severity of symptoms.
  • Tropisetronwas also first described in 1984.[13]It is available in several countries, such as the UK, Australia and France, but not in the United States. The effects of tropisetron last up to 24 hours, so it only requires once-daily administration.
  • Granisetronwas developed around 1988.[14]It is available in the U.S., UK, Australia and other countries.Clinical trialssuggest that it is more effective than other 5-HT3antagonists in preventingdelayedCINV (nausea and vomiting that occur more than 24 hours after the first dose of chemotherapy).[15]It is taken once daily.
  • Dolasetronwas first mentioned in the literature in 1989.[16]It is aprodrug,and most of its effects are due to its active metabolite,hydrodolasetron,which is formed in theliverby theenzymecarbonyl reductase.Dolasetron was approved by the FDA in 1997, and is also administered once daily.
  • Palonosetronis the newest 5-HT3antagonist to become available in the U.S. market. It is anisoquinolinederivative, and is effective in preventing delayed CINV.[17]Palonosetron was approved by the FDA in 2003,[18]initially forintravenous use.An oral formulation was approved on August 22, 2008, for prevention of acute CINV alone, as a large clinical trial did not show oral administration to be as effective as IV use against delayed CINV.[19]
  • Ramosetronis only available in Japan and certainSoutheast Asiancountries as of 2008.[20]It has higheraffinityfor the 5-HT3receptor than the older 5-HT3antagonists, and maintains its effects over two days; it is thereforesignificantlymore effective for delayed CINV.[21]In animal studies, ramosetron was also effective againstirritable bowel syndrome-like symptoms.[22]

Alosetronandcilansetron—the latter was developed bySolvaybut never approved by the FDA —are not antiemetics; instead, they are indicated in the treatment of a subset of irritable bowel syndrome where diarrhea is the dominant symptom. Alosetron was withdrawn from the U.S. market in 2000 due to unacceptably frequent severe side effects, includingischemic colitis,and is only available through a restrictive program to patients who meet certain requirements.[23]

Certainprokineticdrugs such ascisapride,renzaprideandmetoclopramide,although not 5-HT3antagonists proper, possess some weak antagonist effect at the 5-HT3receptor.Galanolactone,aditerpenoidfound inginger,is a 5-HT3antagonist and is believed to at least partially mediate the anti-emetic activity of this plant.[24][25]Mirtazapineis a tetracyclic antidepressant with 5-HT2and 5-HT3antagonist effects that also possesses strong anti-emetic properties, however it is also very sedating. Studies show that Mirtazapine is as equally effective in treating chemotherapy-related nausea and vomiting as standard treatments; it is also cheaper and has fewer side effects than typical anti-emetics, and its antidepressant qualities may be an added benefit for cancer populations.[26]Mirtazapine has also been used in the treatment of the motility disordergastroparesisdue to its anti-emetic effects.[27]Olanzapine,anatypical antipsychoticwith anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.[26]

Adverse effects[edit]

There are fewside effectsrelated to the use of 5-HT3antagonists; the most common areconstipationordiarrhea,headache,anddizziness.[28]Unlikeantihistamineswith antiemetic properties such ascyclizine,5-HT3antagonists do not producesedation,nor do they causeextrapyramidal effects,asphenothiazines(such asprochlorperazine) sometimes do.

All 5-HT3antagonists have been associated withasymptomaticelectrocardiogramchanges, such as prolongation of the PT and QTc intervals and certainarrhythmias.[28]The clinical significance of these side effects is unknown.

Pharmacology[edit]

Mechanism of action[edit]

The 5-HT3receptors are present in several critical sites involved in emesis, includingvagalafferents,thesolitary tract nucleus(STN), and the area postrema itself.Serotoninis released by theenterochromaffincellsof thesmall intestinein response tochemotherapeuticagents and may stimulate vagal afferents (via 5-HT3receptors) to initiate the vomiting reflex. The 5-HT3receptor antagonists suppress vomiting and nausea by inhibiting serotonin binding to the 5-HT3receptors. The highest concentration of 5-HT3receptors in thecentral nervous system(CNS) are found in theSTNandchemoreceptor trigger zone(CTZ), and 5-HT3antagonists may also suppress vomiting and nausea by acting at these sites.[29]The 5-HT3antagonists are greatly selective and have little affinity for other receptors, such asdopamine,histamineandmuscarinic acetylcholine receptors.[28]

Pharmacokinetics[edit]

All 5-HT3antagonists are well-absorbed and effective after oral administration,[4][28]and all are metabolized in theliverby variousisoenzymesof thecytochrome P450system. They do not, however,inhibitorinducethese enzymes.[28]

Comparative pharmacology[edit]

Despite that the 5-HT3receptor antagonists share theirmechanism of action,they have differentchemical structuresand exhibit differences in affinity for thereceptor,dose response and duration of effect. They are alsometabolizedin different ways, that is, different components of thecytochrome P450(CYP) system predominate in themetabolismof the antagonists.[30]

Because of this, patients who are resistant to oneantagonistmight benefit from another. A correlation exists between the number of active CYP 2D6allelesand the number of vomiting episodes by patients who receive treatment withcisplatinand ondansetron ortropisetron.Patients with multiple alleles tend to be unresponsive to theantiemeticdrug and vice versa.[31]

Comparative pharmacology of 5-HT3receptor antagonist[29]
Drug Chemical
nature 		Receptor antagonists T1/2(h) Metabolism Dose
Ondansetron Carbazolederivative 5-HT3receptor antagonist and weak5-HT4antagonist 3.9 hours CYP1A1/2,CYP2D6,CYP 3A3/4/5 150 μg/kg
Granisetron Indazole 5-HT3receptor antagonist 9–11.6 hours CYP3A3/4/5 10 μg/kg
Dolasetron Indole 5-HT3receptor antagonist 7–9 hours CYP 3A3/4/5,CYP2D6 600 – 3000 μg/kg
Palonosetron Isoquinoline 5-HT3receptor antagonist; highest affinity for 5-HT3receptor in this class 40 hours CYP1A2,CYP2D6,CYP3A3/4/5[32] 0.25 mg dose
Ramosetron Benzimidazolederivative 5-HT3receptor antagonist 5.8 hours 300 μg/kg
Tropisetron[30] Indole 5-HT3receptor antagonist 5.6 hours CYP 3A3/4/5,CYP2D6 200 μg/kg
Vortioxetine(Trintellix) Indole 5-HT3receptor antagonist Antidepressant 66h CYP 2D6/2A6/CYP2B6/CYP2C8/9,CYP2C19 5 mg, 10 mg, 20 mg doses

History[edit]

The history of the 5-HT3receptor antagonists began in 1957, when John Gaddum and Zuleika P. Picarelli at theUniversity of Edinburghproposed the existence of two serotonin receptor subtypes, theMandDreceptors (thus named because their function could be blocked bymorphineanddibenzylinerespectively).[33]The 5-HT3receptor was later found to correspond to the M receptor.[34]In the 1970s, John Fozard found thatmetoclopramideandcocainewere weak antagonists at the 5-HT3(5-HT-M) receptor. Fozard and Maurice Gittos later synthesized MDL 72222, the first potent and truly selective 5-HT3receptor antagonist.[35][36]The antiemetic effects of metoclopramide were found to be partially because of its serotonin antagonism.[30]

While Fozard was investigating cocaine analogues, researchers atSandozidentified the potent, selective 5-HT3receptor antagonist ICS 205-930 from which the first marketed selective 5-HT3receptor antagonistsondansetronandgranisetronwere developed, and approved in 1991 and 1993 respectively.[35][37]Several compounds related to MDL 72222 were synthesized which eventually resulted in approval of tropisetron in 1994 and dolasetron in 1997.[37]A new and improved 5-HT3receptor antagonist, named palonosetron, was approved in 2003.[37] The development of selective 5-HT3receptor antagonists was a dramatic improvement in thetreatmentof nausea and vomiting.[30]Ondansetron, granisetron, dolasetron and palonosetron are currently approved in the United States, and form the cornerstone of therapy for the control of acuteemesiswith chemotherapy agents with moderate to high emetogenic potential.[38]

Development[edit]

5-HT3receptor antagonists or serotoninantagonistswere first introduced in the early 1990s, and they have become the most widely used antiemetic drugs inchemotherapy.[29]They have also been proven safe and effective for treatment ofpostoperative nausea and vomiting.[30]Serotonin (5-HT) is found widely distributed throughout thegutand thecentral nervous system.In the gut,5-HTis found mostly inmucosalenterochromaffincells.Enterochromaffin cells are sensory transducers that release5-HTto activateintrinsic(via 5-HT1P and 5-HT4receptors) andextrinsic(via 5-HT3receptors) primaryafferent nerves.[39]Chemotherapeutic drugs for malignant disorders that cause vomiting have been found to cause release of large amounts of serotonin from enterochromaffin cells in the gut, serotonin acts on 5-HT3receptors in the gut and brain stem.[39]

Drug design[edit]

Experiments have shown evidence that the ligand-binding site is located at the interface of two adjacent subunits.[40]The ligand binding site is formed by three loops (A-C) from the principal ligand binding subunit (principal face) and three β-strands (D-F) from the adjacent subunit (complementary face).[34][41]The amino acid residue E129 on loop A faces into the binding pocket and forms a critical hydrogen bond with the hydroxyl group of 5-HT. Loop B contains W183, a criticaltryptophanligand binding residue that contributes to a cation-π interaction between the pielectrondensity of tryptophan and the primary amine of 5-HT. Loop C residues have been considered as candidates for the differingpharmacologyofrodentandhuman5-HT3receptors because of their divergence between species. The most importantaromaticresidue within loop C is probably Y234 that lies opposite to the loop Btryptophanin the ligand binding pocket and is involved in ligand binding. Loops D and F are in fact β-strands not loops. W90 in loop D is critical for ligand binding and antagonists may directly contact R92. The azabicyclic ring of the competitiveantagonistgranisetron is located close to W183 forming a cation-pi interaction.[42]Loop E residues Y143, G148, E149, V150, Q151, N152, Y153 and K154 may be important for granisetron binding. The structure of loop F has yet to be clarified but W195 and D204 seem to be critical for ligand binding.[34]

Binding affinity of 5-HT3receptor antagonist[43]
5-HT3receptor antagonists Binding affinity (Kd,Ki,K50) Species
Tropisetron 11 nM Human
Granisetron 1.44 nM Human
Ondansetron 4.9 nM Human
Palonosetron 31.6 nM Rat cerebral cortex, rabbit ileal myenteric plexus, guinea-pig ileal plexus
Dolasetron 20.03 nM NG 108-15
Metoclopramide (non-selective) 355 nM Human
Cocaine 2.45-83 nM Rat-rabbit

Pharmacophore scaffold[edit]

Fig 1. Ondansetron: First generation 5-HT3receptor antagonist
Fig 2. Palonosetron: Second generation 5-HT3receptor antagonist

Chemical structures of the first generation 5-HT3receptor antagonist can be categorized to three main classes[30]

  1. Carbazolederivatives (ondansetron)
  2. Indazoles(Granisetron)
  3. Indoles(TropisetronandDolasetron)

The first-generation 5-HT3receptor antagonist (ondansetron,dolasetron,granisetron, andtropisetron) have been the most important drugs in antiemetic therapy for emetogenicchemotherapy.They are especially effective in treating acuteemesis,occurring in the first 24 hours followingchemotherapy.[38] A newer drugpalonosetronis a pharmacologically distinct and highly selective, second generation 5-HT3receptor antagonist.[44]Palonosetronhas twostereogeniccenters and exists as fourstereoisomers.[44] Palonosetron has longer half-life (40h) and greater receptor binding affinity (>30 fold; when compared to first generation antagonists).[38]

Pharmacophore[edit]

Fig 3. The 5-HT3receptor antagonists pharmacophore (schematic)

Thepharmacophoreof 5-HT3receptors consists of three components: a carbonyl-containing linking moiety,aromatic/heteroaromaticring, and a basic center. Thecarbonylgroup is coplanar to thearomatic ring.5-HT3receptor antagonists are more likely to bind in their protonated form.[45]Docking of a range of antagonists into a homology model of the5-HT3receptorbinding site shows a reasonably good agreement with thepharmacophoremodel and supports the observed differences between species. Studies of granisetron in the binding pocket revealed that thearomaticrings of granisetron lie between W183 and Y234 and the azabicyclic ring between W90 and F226. In this study another energetically favorable location of granisetron was identified, closer to the membrane, on a position that could be a part of a binding/unbinding pathway for the ligand. A similarly located alternative binding site for granisetron has since been identified in another study of the 5-HT3receptor.[43]

Structure-activity relationship[edit]

Fig 4. The main pharmacophoric elements of the known 5-HT3antagonist

5-HT3receptor antagonists share the samepharmacophore.[43]An aromatic moiety (preferably indole), a linking acyl group capable ofhydrogen bondinginteractions, and a basicamine(nitrogen) can be regarded as the keypharmacophoricelements of the known 5-HT3receptor antagonists. There are steric limitations of thearomaticbinding site and although two hydrogen-bonding interactions are possible on theheterocycliclinking group (oxadiazole capable of accepting two hydrogen bonds), only one is essential for high affinity. An optimal environment of the basic nitrogen is when its constrained within an azabicyclic system with the highest affinity observed for systems with nitrogen at the bridgehead position and secondaryaminesbeing more potent.[46]The 5-HT3 receptor can only accommodate small substituents on the charged amine, amethylgroup being optimal.[43]The optimal distance between the aromatic binding site and the basic amine is 8,4-8,9 Å and it is best if a two-carbon linkage separates the oxadiazole and the nitrogen. An increasing substitution of R increases affinity.[46]The mostpotentantagonists of 5-HT3receptors have a 6-memberedaromaticring, and they usually have 6,5heterocyclicrings.[43]No correlation has been found between thelipophilicityof compounds and the 5-HT3receptor affinities.[47]Since most of the known 5-HT3 antagonists are ester or amide derivatives they are potentially susceptible to hydrolysis, which could be avoided by incorporating H-bond acceptors within a 5-membered heteroaromatic ring.[46]

Fig 5. The importance of C5 (R1) and C7 (R2) substitution has been studied

Structure-activity relationship(SAR) studies ofLGICreceptor ligands are valuable to investigate their structure and function. Anantagonist-like molecule with low intrinsic activity (ia) decreases the frequency of channel-opening and the permeability of ions. Small lipophilic C5 (R1) (see fig. 5) substituents afford compounds with potent antagonism which indicates that the C5 substituent may fit in a narrow,hydrophobicgroove of the binding region in the receptor. It seems that the amino acid residues that interact with the C7 (R2) substituents have little to do with ligand binding but play a big role in ion channel gating. Sterically bulky substituents show a greater interaction with the gatingamino acidresidues and favor the open conformation of the ion channel because of sterical repulsion.[48]

Fig 6. The carbonyl group is completely coplanar with the adjacent aromatic ring

Ondansetron is aracematebut thestereochemistryof the asymmetriccarbonatomis not an important factor in the 5-HT3receptor interaction. Annelation of the 1,7-positions of the indole nucleus of ondansetron results in increased affinity for thereceptor.[49]

A methyl- group appears to be as effective functionally as a chlorine in the R position (see fig. 6). Thecarbonylgroup is responsible for a strong interaction with the receptor and contributes significantly to the binding process. This carbonyl group is completelycoplanarwith the adjacentaromaticring, indicating that the receptor-bound conformation corresponds to one of the most stable conformations of this group in the flexible compounds.[45]

Research[edit]

A small,open-label trialcarried out in 2000 found ondansetron to be useful in treatingantipsychotic-inducedtardive dyskinesiain people withschizophrenia.[50][51] The study's patients also showedsignificantimprovement in the disease's symptoms; a laterdouble-blind,randomized controlled trialalso found ondansetron to significantly improve schizophrenia symptoms when used as an adjunct tohaloperidol,and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol.[52]

See also[edit]

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