View source for 5-HT3 antagonist

{{Short description|Anti-nausea group of medications}}
{{DISPLAYTITLE:5-HT<sub>3</sub> antagonist}}
{{Infobox drug class
| Name             = 5-HT<sub>3</sub> receptor antagonist
| Image            = Ondansetron skeletal.svg
| ImageClass       = skin-invert-image
| Caption          = [[Skeletal formula]] of [[ondansetron]], the prototypical 5-HT<sub>3</sub> antagonist
| Use              = [[Nausea]] and [[Vomiting]]
| Biological_target = [[5-HT3 receptor|5-HT<sub>3</sub> receptor]]
| ATC_prefix       = A04AA
| MeshID           = D058831
| Drugs.com        = {{Drugs.com|drug-class|5ht3-receptor-antagonists}}
| Consumer_Reports = drugs-to-treat-nausea-and-vomiting
}}

The '''5-HT<sub>3</sub> antagonists''', informally known as "'''setrons'''", are a [[Drug class|class of drugs]] that act as [[receptor antagonist]]s at the [[5-HT3 receptor|5-HT<sub>3</sub> receptor]], a subtype of [[serotonin]] [[5-HT receptor|receptor]] found in terminals of the [[vagus nerve]] and in certain areas of the brain.
With the notable exceptions of [[alosetron]] and [[cilansetron]], which are used in the treatment of [[irritable bowel syndrome]], all 5-HT<sub>3</sub> antagonists are [[antiemetic]]s, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by [[chemotherapy|cancer chemotherapy]] and are considered the gold standard for this purpose.<ref>{{cite journal |vauthors=de Wit R, Aapro M, Blower PR |title=Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients? |journal=Cancer Chemother Pharmacol |volume=56 |issue=3 |pages=231–8 |year=2005 |pmid=15838653 |doi=10.1007/s00280-005-1033-0|s2cid=27576150 }}</ref>

The 5-HT<sub>3</sub> antagonists may be identified by the suffix '''-setron''',<ref>[[World Health Organization]] (2006). {{cite web|url=https://www.who.int/medicines/services/inn/RevisedFinalStemBook2006.pdf |title=''The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances'' }}&nbsp;{{small|(703&nbsp;[[Kibibyte|KiB]])}}. Geneva: WHO Press. Retrieved on 2007-05-15.</ref> and are classified under code [[ATC code A04|A04AA]] of the {{abbr|[[World Health Organization|WHO]]|World Health Organization}}'s [[Anatomical Therapeutic Chemical Classification System]].

==Medical uses==
5-HT<sub>3</sub> antagonists are most effective in the prevention and treatment of [[chemotherapy-induced nausea and vomiting]] (CINV), especially that caused by highly [[emesis|emetogenic]] drugs such as [[cisplatin]]; when used for this purpose, they may be given alone or, more frequently, with a [[glucocorticoid]], usually [[dexamethasone]]. They are usually given [[intravenous therapy|intravenously]], shortly before administration of the chemotherapeutic agent,<ref name="ESMO">{{cite journal|title="ESMO Minimum Clinical Recommendations for prophylaxis of chey-induced nausea and vomiting (NV)". |journal=Annals of Oncology |volume=16 |pages=i77–i79 |doi=10.1093/annonc/mdi805 |pmid=15888767 |year=2005 |last1=Herrstedt |first1=J. |last2=Aapro |first2=M. S. |last3=Roila |first3=F. |last4=Kataja |first4=V. V. |author5=ESMO Guidelines Task Force |doi-access=free }}</ref> although some authors have argued that oral administration may be preferred.<ref name="pmid11006796">{{cite journal |vauthors=Lindley C, Blower P |title=Oral serotonin type 3-receptor antagonists for prevention of chemotherapy-induced emesis |journal=Am J Health-Syst Pharm |volume=57 |issue=18 |pages=1685–97 |year=2000 |pmid=11006796 |doi=10.1093/ajhp/57.18.1685|doi-access=free }} [https://www.medscape.com/viewarticle/406912 Free full text with registration at Medscape]</ref>
The concomitant administration of a [[NK1 receptor antagonist|NK<sub>1</sub> receptor antagonist]], such as [[aprepitant]], [[statistical significance|significantly]] increases the efficacy of 5-HT<sub>3</sub> antagonists in preventing both acute and delayed CINV.<ref name="pmid16608997">{{cite journal |vauthors=Roila F, Fatigoni S |title=New antiemetic drugs |journal=Ann Oncol |volume=17 |pages=ii96–100 |year=2006 |issue=Suppl 2 |pmid=16608997 |doi=10.1093/annonc/mdj936|doi-access=free }}</ref>

The 5-HT<sub>3</sub> antagonists are also indicated in the prevention and treatment of [[radiation therapy|radiation-induced]] nausea and vomiting (RINV), when needed, and [[postoperative 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-HT<sub>3</sub> antagonists are ineffective in controlling [[motion sickness]].<ref>{{cite journal |vauthors=Stott JR, Barnes GR, Wright RJ, Ruddock CJ |title=The effect on motion sickness and oculomotor function of GR 38032F, a 5-HT3-receptor antagonist with anti-emetic properties |journal=British Journal of Clinical Pharmacology |volume=27 |issue=2 |pages=147–57 |year=1989 |pmid=2523720 |doi= 10.1111/j.1365-2125.1989.tb05345.x|pmc=1379774}}</ref><ref>{{cite journal |vauthors=Levine ME, Chillas JC, Stern RM, Knox GW |title=The effects of serotonin (5-HT3) receptor antagonists on gastric tachyarrhythmia and the symptoms of motion sickness |journal=Aviat Space Environ Med |volume=71 |issue=11 |pages=1111–4 |year=2000 |pmid=11086664 }}</ref><ref>{{cite journal |vauthors=Muth ER, Elkins AN |title=High dose ondansetron for reducing motion sickness in highly susceptible subjects |journal=Aviat Space Environ Med |volume=78 |issue=7 |pages=686–92 |date=July 2007 |pmid=17679566}}</ref> A [[randomized controlled trial|randomized, placebo-controlled trial]] of ondansetron to treat motion sickness in [[air ambulance]] personnel showed subjective improvement, but it was not [[statistical significance|statistically significant]].<ref>Dula D, Rosenbach S (2006). [http://www.allacademic.com/meta/p_mla_apa_research_citation/0/5/5/9/5/p55953_index.html "A randomized clinical trial comparing ondansetron with placebo in aeromedical {{sic|per|sonel|hide=y}} with motion sickness".] Paper presented at the annual meeting of the National Association of EMS Physicians, Registry Resort, Naples, FL, January 19–21, 2006. Retrieved on April 25, 2009.</ref>

===Available agents===
*'''[[Ondansetron]]''' was the first 5-HT<sub>3</sub> antagonist, developed by [[Glaxo]] around 1984. Its efficacy was first established in 1987, in animal models,<ref>{{cite journal |vauthors=Hagan RM, Butler A, Hill JM, Jordan CC, Ireland SJ, Tyers MB |title=Effect of the 5-HT3 receptor antagonist, GR38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of the rat brain |journal=Eur. J. Pharmacol. |volume=138 |issue=2 |pages=303–5 |year=1987 |pmid=2442006 |doi=10.1016/0014-2999(87)90450-X}}</ref><ref>{{cite journal |vauthors=Costall B, Gunning SJ, Naylor RJ, Tyers MB |title=The effect of GR38032F, novel 5-HT3-receptor antagonist on gastric emptying in the guinea-pig |journal=Br. J. Pharmacol. |volume=91 |issue=2 |pages=263–4 |year=1987 |pmid=2955843 |doi= 10.1111/j.1476-5381.1987.tb10280.x|pmc=1853517}}</ref> and it was extensively studied over the following years.<ref>See ''Eur J Cancer Clin Oncol'' 1989; '''25 Suppl 1'''.</ref> Ondansetron was approved by the U.S. [[Food and Drug Administration]] in 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-HT<sub>3</sub> antagonists available as a [[generic drug]] in the United States. Ondansetron may be given several times daily, depending on the severity of symptoms.
*'''[[Tropisetron]]''' was also first described in 1984.<ref>Donatsch P, Engel G, Richardson BP, Stadler PA (1984). "A highly selective and potent antagonist at
peripheral neuronal 5-hydroxy tryptamine receptors". ''Br J Pharmacol'' '''81''': 34P.</ref> 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.
*'''[[Granisetron]]''' was developed around 1988.<ref>Zussman BD, Clarkeson A, Coates PE, Rapeport WG (1988). "The pharmacokinetic
profile of BRL 43694, a novel 5-HT3 receptor antagonist, in healthy male
volunteers". ''Br J Clin Pharmacol'' '''25''': 107P.</ref> It is available in the U.S., UK, Australia and other countries. [[Clinical trial]]s suggest that it is more effective than other 5-HT<sub>3</sub> antagonists in preventing ''delayed'' CINV (nausea and vomiting that occur more than 24 hours after the first dose of chemotherapy).<ref>{{cite journal |author=Aapro M |title=Granisetron: an update on its clinical use in the management of nausea and vomiting |journal=Oncologist |volume=9 |issue=6 |pages=673–86 |year=2004 |pmid=15561811 |doi=10.1634/theoncologist.9-6-673}} [http://theoncologist.alphamedpress.org/cgi/content/full/9/6/673 Free full text]</ref> It is taken once daily.
*'''[[Dolasetron]]''' was first mentioned in the literature in 1989.<ref name="pmid2744086">{{cite journal |vauthors=Sorensen SM, Humphreys TM, Palfreyman MG |title=Effect of acute and chronic MDL 73,147EF, a 5-HT3 receptor antagonist, on A9 and A10 dopamine neurons |journal=Eur. J. Pharmacol. |volume=163 |issue=1 |pages=115–8 |year=1989 |pmid=2744086 |doi=10.1016/0014-2999(89)90402-0}}</ref> It is a [[prodrug]], and most of its effects are due to its active metabolite, ''hydrodolasetron'', which is formed in the [[liver]] by the [[enzyme]] [[carbonyl reductase (NADPH)|carbonyl reductase]]. Dolasetron was approved by the FDA in 1997, and is also administered once daily.
*'''[[Palonosetron]]''' is the newest 5-HT<sub>3</sub> antagonist to become available in the U.S. market. It is an [[isoquinoline]] derivative, and is effective in preventing delayed CINV.<ref name="pmid17106506">{{cite journal |author=De Leon A |title=Palonosetron (Aloxi): a second-generation 5-HT3 receptor antagonist for chemotherapy-induced nausea and vomiting |journal=Proceedings (Baylor University. Medical Center) |volume=19 |issue=4 |pages=413–6 |year=2006 |pmid=17106506 |doi= 10.1080/08998280.2006.11928210|pmc=1618755}}</ref> Palonosetron was approved by the FDA in 2003,<ref>{{cite press release | url =  http://www.docguide.com/news/content.nsf/news/8525697700573E1885256D71004DE600 | title = FDA Approves Aloxi (Palonosetron) For Treatment of Chemotherapy-Related Nausea and Vomiting | date = July 28, 2003 | access-date = 2007-05-15 | publisher = Doctor's Guide Publishing Limited}}</ref> initially for [[intravenous therapy|intravenous 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.<ref>{{cite web |url=http://www.medscape.com/viewarticle/580032 |title=FDA Approvals: Nplate, Aloxi, Vidaza |author=Waknine, Yael |date=September 4, 2008 |access-date=2008-09-04 |publisher=[[Medscape]]| archive-url= https://web.archive.org/web/20081202194048/http://www.medscape.com/viewarticle/580032| archive-date=December 2, 2008| url-status= live}} Freely available with registration.</ref>
*'''[[Ramosetron]]''' is only available in Japan and certain [[Southeast Asia]]n countries as of 2008.<ref>[http://www.mims-online.com/Page.aspx?menuid=mng&name=Nasea+amp   Abridged prescribing information - Nasea (MIMS Philippines)]{{Dead link|date=April 2023 |bot=InternetArchiveBot |fix-attempted=yes }}. Retrieved on June 13, 2008.</ref> It has higher [[Receptor antagonist#Affinity|affinity]] for the 5-HT<sub>3</sub> receptor than the older 5-HT<sub>3</sub> antagonists, and maintains its effects over two days; it is therefore [[statistical significance|significantly]] more effective for delayed CINV.<ref>{{cite journal |author=Rabasseda X |title=Ramosetron, a 5-HT3 receptor antagonist for the control of nausea and vomiting |journal=Drugs of Today |volume=38 |issue=2 |pages=75–89 |date=February 2002 |pmid=12532186 |doi=10.1358/dot.2002.38.2.820104 }}</ref> In animal studies, ramosetron was also effective against [[irritable bowel syndrome]]-like symptoms.<ref>{{cite journal |vauthors=Hirata T, Funatsu T, Keto Y, Nakata M, Sasamata M |title=Pharmacological profile of ramosetron, a novel therapeutic agent for IBS |journal=Inflammopharmacology |volume=15 |issue=1 |pages=5–9 |date=February 2007 |pmid=17323187 |doi=10.1007/s10787-006-1537-1 |s2cid=29179265 }}</ref>

[[Alosetron]] and [[cilansetron]]—the latter was developed by [[Solvay (company)|Solvay]] but 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, including [[ischemic colitis]], and is only available through a restrictive program to patients who meet certain requirements.<ref>[[GlaxoSmithKline]] (2005). {{cite web|url= https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021107s012lbl.pdf |archive-url= https://web.archive.org/web/20121016134837/http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021107s012lbl.pdf |url-status= dead |archive-date= October 16, 2012 |title=Lotronex Prescribing Information }}&nbsp;{{small|(203&nbsp;[[Kibibyte|KiB]])}}. U.S. [[Food and Drug Administration]]. Retrieved on 2009-07-30.</ref>

Certain [[prokinetic]] drugs such as [[cisapride]], [[renzapride]] and [[metoclopramide]], although not 5-HT<sub>3</sub> antagonists proper, possess some weak antagonist effect at the 5-HT<sub>3</sub> receptor. [[Galanolactone]], a [[terpenoid|diterpenoid]] found in [[ginger]], is a 5-HT<sub>3</sub> antagonist and is believed to at least partially mediate the anti-emetic activity of this plant.<ref>Ku, Valerie (2003). [http://www.uchsc.edu/sop/pharmd/8.Experiential_Programs/-downloads/ginger.pdf Ginger]{{Dead link|date=September 2018 |bot=InternetArchiveBot |fix-attempted=yes }}. [[University of Colorado at Denver and Health Sciences Center|University of Colorado at Denver and Health Sciences Center School of Pharmacy]]. Retrieved on 2007-10-25.</ref><ref>{{cite journal |author=Huang QR |title=Anti-5-hydroxytryptamine3 effect of galanolactone, diterpenoid isolated from ginger |journal=Chem Pharm Bull |volume=39 |issue=2 |pages=397–9 |year=1991 |pmid=2054863 |doi= 10.1248/cpb.39.397|author2=Iwamoto M |author3=Aoki S |display-authors=3 |last4=Tanaka |first4=N |last5=Tajima |first5=K |last6=Yamahara |first6=J |last7=Takaishi |first7=Y |last8=Yoshida |first8=M |last9=Tomimatsu |first9=T|doi-access=free }}</ref> [[Mirtazapine]] is a tetracyclic antidepressant with 5-HT<sub>2</sub> and 5-HT<sub>3</sub> antagonist 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.<ref name="Kast">{{cite journal | author=Kast R E | title=Cancer chemotherapy and cachexia: mirtazapine and olanzapine are 5-HT3 antagonists with good antinausea effects | url=http://www3.interscience.wiley.com/cgi-bin/fulltext/117989553/PDFSTART | journal=European Journal of Cancer Care | volume=16 | year=2007 | pages=351–354 | doi=10.1111/j.1365-2354.2006.00760.x | pmid=17587360 | last2=Foley | first2=KF | issue=4 | url-access=subscription }}{{dead link|date=February 2019|bot=medic}}{{cbignore|bot=medic}}</ref>  Mirtazapine has also been used in the treatment of the motility disorder [[gastroparesis]] due to its anti-emetic effects.<ref>{{cite journal | author=Kim S | title=Mirtazapine for Severe Gastroparesis Unresponsive to Conventional Prokinetic Treatment | journal=Psychosomatics | volume=47 | year=2006 | pages=440–442 | doi=10.1176/appi.psy.47.5.440 | pmid=16959934 | last2=Shin | first2=IS | last3=Kim | first3=JM | last4=Kang | first4=HC | last5=Mun | first5=JU | last6=Yang | first6=SJ | last7=Yoon | first7=JS | issue=5 | doi-access=free }}</ref> [[Olanzapine]], an [[atypical antipsychotic]] with anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.<ref name="Kast"/>

==Adverse effects==
There are few [[adverse drug reaction|side effects]] related to the use of 5-HT<sub>3</sub> antagonists; the most common are [[constipation]] or [[diarrhea]], [[headache]], and [[dizziness]].<ref name="Oregon">{{cite web | url = http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/reviews/articles/dur_review_2003_02_11_hydroxytryptamine3.pdf | title = 5-Hydroxytryptamine3 (5-HT<sub>3</sub>) Receptor Antagonists | year = 2003 | publisher = [[Oregon State University]] College of Pharmacy | access-date = 2007-05-15 | archive-url = https://web.archive.org/web/20130313220035/http://pharmacy.oregonstate.edu/drug_policy/pages/dur_board/reviews/articles/dur_review_2003_02_11_hydroxytryptamine3.pdf | archive-date = 2013-03-13 | url-status = dead }}</ref> Unlike [[antihistamine]]s with antiemetic properties such as [[cyclizine]], 5-HT<sub>3</sub> antagonists do not produce [[sedation]], nor do they cause [[extrapyramidal effects]], as [[phenothiazine]]s (such as [[prochlorperazine]]) sometimes do.

All 5-HT<sub>3</sub> antagonists have been associated with [[wikt:asymptomatic|asymptomatic]] [[electrocardiogram]] changes, such as prolongation of the PT and QTc intervals and certain [[cardiac arrhythmia|arrhythmia]]s.<ref name="Oregon"/> The clinical significance of these side effects is unknown.

==Pharmacology==
===Mechanism of action===
The 5-HT<sub>3</sub> receptors are present in several critical sites involved in emesis, including [[Vagus nerve|vagal]] [[Afferent nerve|afferents]], the [[solitary tract nucleus]] (STN), and the area postrema itself. [[Serotonin]] is released by the [[Enterochromaffin cell|enterochromaffin]] [[Cell (biology)|cells]] of the [[small intestine]] in response to [[chemotherapeutic]] agents and may stimulate vagal afferents (via 5-HT<sub>3</sub> receptors) to initiate the vomiting reflex. The 5-HT<sub>3</sub> receptor antagonists suppress vomiting and nausea by inhibiting serotonin binding to the 5-HT<sub>3</sub> receptors. The highest concentration of 5-HT<sub>3</sub> receptors in the [[central nervous system]] ([[Central nervous system|CNS]]) are found in the [[Solitary tract nucleus|STN]] and [[chemoreceptor trigger zone]] (CTZ), and 5-HT<sub>3</sub> antagonists may also suppress vomiting and nausea by acting at these sites.<ref name="Brunton_2006"/> The 5-HT<sub>3</sub> antagonists are greatly selective and have little affinity for other receptors, such as [[dopamine receptor|dopamine]], [[histamine receptor|histamine]] and [[muscarinic acetylcholine receptor]]s.<ref name="Oregon" />

===Pharmacokinetics===
All 5-HT<sub>3</sub> antagonists are well-absorbed and effective after oral administration,<ref name="pmid11006796"/><ref name="Oregon"/> and all are metabolized in the [[liver]] by various [[isoenzyme]]s of the [[cytochrome P450]] system. They do not, however, [[enzyme inhibitor|inhibit]] or [[enzyme induction and inhibition|induce]] these enzymes.<ref name="Oregon"/>

===Comparative pharmacology ===
Despite that the 5-HT<sub>3</sub> receptor antagonists share their [[mechanism of action]], they have different [[chemical structure]]s and exhibit differences in affinity for the [[Receptor (biochemistry)|receptor]], dose response and duration of effect. They are also [[metabolized]] in different ways, that is, different components of the [[cytochrome P450]] ([[Cytochrome P450|CYP]]) system predominate in the [[metabolism]] of the antagonists.<ref name = "Gan_2005"/>

Because of this, patients who are resistant to one [[antagonist]] might benefit from another. A correlation exists between the number of active CYP 2D6 [[alleles]] and the number of vomiting episodes by patients who receive treatment with [[cisplatin]] and ondansetron or [[tropisetron]]. Patients with multiple alleles tend to be unresponsive to the [[antiemetic]] drug and vice versa.<ref name="Sanger_2008">{{cite journal |author = Sanger GJ|title = 5-hydroxytryptamine and the gastrointestinal tract: where next?|journal = Trends in Pharmacological Sciences|volume = 29|issue = 9|pages = 465–71|date = September 2008|pmid = 19086255|doi = 10.1016/j.tips.2008.06.008}}</ref>

{| class="wikitable"
|+ Comparative pharmacology of 5-HT<sub>3</sub> receptor antagonist<ref name="Brunton_2006"/>
|-
! [[Medications|Drug]]
! Chemical<br /> nature
! [[Receptor antagonist]]s
![[Elimination half-life|T<sub>1/2</sub>]] (h)
! [[Metabolism]]
! [[Dose (biochemistry)|Dose]]
|-
| [[Ondansetron]]
| [[Carbazole]] derivative
| 5-HT<sub>3</sub> receptor antagonist and weak [[5-HT4 receptor|5-HT<sub>4</sub>]] antagonist
| 3.9 hours
| [[CYP1A1]]/[[CYP1A2|2]], [[CYP2D6]], CYP 3A3/[[CYP3A4|4]]/[[CYP3A5|5]]
| 150 &nbsp;μg/kg
|-
| [[Granisetron]]
| [[Indazole]]
| 5-HT<sub>3</sub> receptor antagonist
| 9–11.6 hours
| CYP3A3/[[CYP3A4|4]]/[[CYP3A5|5]]
| 10 &nbsp;μg/kg
|-
|[[Dolasetron]]
|[[Indole]]
|5-HT<sub>3</sub> receptor antagonist
|7–9 hours
|CYP 3A3/[[CYP3A4|4]]/[[CYP3A5|5]], [[CYP2D6]]
|600 – 3000 &nbsp;μg/kg
|-
|[[Palonosetron]]
|[[Isoquinoline]]
|5-HT<sub>3</sub> receptor antagonist; highest affinity for 5-HT<sub>3</sub> receptor in this class
|40 hours
|[[CYP1A2]], [[CYP2D6]], CYP3A3/[[CYP3A4|4]]/[[CYP3A5|5]]<ref name = Aapro_2005>{{cite journal |author=Aapro M |title=5-HT(3)-receptor antagonists in the management of nausea and vomiting in cancer and cancer treatment |journal=Oncology |volume=69 |issue=2 |pages=97–109 |year=2005 |pmid=16131816 |doi=10.1159/000087979|s2cid=71759860 }}</ref>
|0.25 &nbsp;mg dose
|-
|[[Ramosetron]]
|[[Benzimidazole]] derivative
|5-HT<sub>3</sub> receptor antagonist
|5.8 hours
|
|300 &nbsp;μg/kg
|-
|[[Tropisetron]]<ref name="Gan_2005" />
|[[Indole]] 
|5-HT<sub>3</sub> receptor antagonist
|5.6 hours
|CYP 3A3/[[CYP3A4|4]]/[[CYP3A5|5]], [[CYP2D6]]
|200 &nbsp;μg/kg
|-
|[[Vortioxetine]]
|[[Phenylpiperazine]] 
|5-HT<sub>3</sub> receptor antagonist Antidepressant
|66h
|CYP 2D6/ [[2A6]]/[[CYP2B6]]/[[CYP2C8/9]], [[CYP2C19]]
|5 &nbsp;mg, 10 &nbsp;mg, 20 &nbsp;mg doses
|}

==History==
The history of the 5-HT<sub>3</sub> receptor antagonists began in 1957, when John Gaddum and Zuleika P. Picarelli at the [[University of Edinburgh]] proposed the existence of two serotonin receptor subtypes, the ''M'' and ''D'' receptors (thus named because their function could be blocked by [[morphine]] and [[phenoxybenzamine|dibenzyline]] respectively).<ref>{{cite journal |vauthors=GADDUM JH, PICARELLI ZP |title=Two kinds of tryptamine receptor |journal=[[British Journal of Pharmacology and Chemotherapy]] |volume=12 |issue=3 |pages=323–8 |date=September 1957 |pmid=13460238 |pmc=1509685 |doi=10.1111/j.1476-5381.1957.tb00142.x}}</ref> The 5-HT<sub>3</sub> receptor was later found to correspond to the M receptor.<ref name = Barnes_2008>{{cite journal |vauthors=Barnes NM, Hales TG, Lummis SC, Peters JA |title=The 5-HT3 receptor--the relationship between structure and function |journal=Neuropharmacology |volume=56 |issue=1 |pages=273–84 |date=January 2009 |pmid=18761359 |pmc=6485434 |doi=10.1016/j.neuropharm.2008.08.003}}</ref> In the 1970s, John Fozard found that [[metoclopramide]] and [[cocaine]] were weak antagonists at the 5-HT<sub>3</sub> (5-HT-M) receptor. Fozard and Maurice Gittos later synthesized MDL 72222, the first potent and truly selective 5-HT<sub>3</sub> receptor antagonist.<ref name=King_1993>{{Cite book | last1 = King | first1 = Frank D. | last2 = Jones | first2 = Brian J. | last3 = Sanger | first3 = Gareth J. |title =5-Hydroxytryptamine-3 Receptor Antagonists | publisher = CRC Press | year = 1993 | pages = 2–3 |isbn =978-0-8493-5463-2 }}</ref><ref name=Galvan_1996>{{Cite journal | last1 = Galvan | first1 = M. | last2 = Gittos | first2 = M. | last3 = Fatmi | first3 = M. | title = DISCOVERY OF 5-HT<sub>3</sub> RECEPTOR ANTAGONISTS AND DOLASETRON MESILATE | journal = EJHP Journal | issue = 6 | pages = 10–11 | date = October 1996 | url = http://www.eahp.eu/EJHP/EJHP-Practice/Issue-6-1996/Science/DISCOVERY-OF-5-HT3-RECEPTOR-ANTAGONISTS-AND-DOLASETRON-MESILATE | access-date = 2010-01-06 | archive-url = https://web.archive.org/web/20110720155235/http://www.eahp.eu/EJHP/EJHP-Practice/Issue-6-1996/Science/DISCOVERY-OF-5-HT3-RECEPTOR-ANTAGONISTS-AND-DOLASETRON-MESILATE | archive-date = 2011-07-20 | url-status = dead }}</ref> The antiemetic effects of metoclopramide were found to be partially because of its serotonin antagonism.<ref name ="Gan_2005"/>

While Fozard was investigating cocaine analogues, researchers at [[Sandoz]] identified the potent, selective 5-HT<sub>3</sub> receptor antagonist ICS 205-930 from which the first marketed selective 5-HT<sub>3</sub> receptor antagonists [[ondansetron]] and [[granisetron]] were developed, and approved in 1991 and 1993 respectively.<ref name ="King_1993"/><ref name = Billio_2008>{{cite journal |first1=Atto |last1=Billio |first2=Mike J. |last2=Clarke |first3=Enrico |last3=Morello |title=Comparison of clinical efficacy of serotonin receptor antagonists in highly emetogenic chemotherapy |journal=Cochrane Database of Systematic Reviews |issue=4 |year=2006 |doi=10.1002/14651858.CD006272 |first4=Atto |last4=Billio |editor1-last=Billio |editor1-first=Atto}}</ref>  Several compounds related to MDL 72222 were synthesized which eventually resulted in approval of tropisetron in 1994 and dolasetron in 1997.<ref name = "Billio_2008" /> A new and improved 5-HT<sub>3</sub> receptor antagonist, named palonosetron, was approved in 2003.<ref name = "Billio_2008" />
The development of selective 5-HT<sub>3</sub> receptor antagonists was a dramatic improvement in the [[therapy|treatment]] of nausea and vomiting.<ref name="Gan_2005"/>  Ondansetron, granisetron, dolasetron and palonosetron are currently approved in the United States, and form the cornerstone of therapy for the control of acute [[emesis]] with chemotherapy agents with moderate to high emetogenic potential.<ref name= Oo_2005>{{cite journal |vauthors=Oo TH, Hesketh PJ |title=Drug insight: New antiemetics in the management of chemotherapy-induced nausea and vomiting |journal=Nature Clinical Practice Oncology |volume=2 |issue=4 |pages=196–201 |date=April 2005 |pmid=16264934 |doi=10.1038/ncponc0132|s2cid=20464189 }}</ref>

===Development===
5-HT<sub>3</sub> receptor antagonists or serotonin [[Receptor antagonist|antagonists]] were first introduced in the early 1990s, and they have become the most widely used antiemetic drugs in [[chemotherapy]].<ref name=Brunton_2006>{{Cite book |last1=Brunton |first1=Laurence L. |last2=Lazo |first2=John S. |last3=Parker |first3=Keith L. |title=Goddman & Gilman's The Pharmacological Basis of Therapeutics |publisher=McGraw-Hill |location=New York  |year=2006 |pages=1000–3 |isbn=978-0-07-142280-2}}</ref> They have also been proven safe and effective for treatment  of [[Postoperative nausea|postoperative nausea and vomiting]].<ref name= Gan_2005>{{cite journal |author=Gan TJ |title=Selective serotonin 5-HT3 receptor antagonists for postoperative nausea and vomiting: are they all the same? |journal=CNS Drugs |volume=19 |issue=3 |pages=225–38 |year=2005 |pmid=15740177 |doi=10.2165/00023210-200519030-00004|s2cid=23209789 }}</ref> Serotonin (5-HT) is found widely distributed throughout the [[Gut (zoology)|gut]] and the [[central nervous system]]. In the gut, [[5-HT]] is found mostly in [[mucosal]] [[Enterochromaffin cell|enterochromaffin]] [[Cell (biology)|cells]]. Enterochromaffin cells are sensory transducers that release [[5-HT]] to activate [[intrinsic]] (via 5-HT1P and 5-HT<sub>4</sub> receptors) and [[extrinsic]] (via 5-HT<sub>3</sub> receptors) primary [[afferent nerves]].<ref name= kamm_2001>{{cite journal |author=Kamm MA |title=Review article: the complexity of drug development for irritable bowel syndrome |journal=Alimentary Pharmacology & Therapeutics |volume=16 |issue=3 |pages=343–51 |date=March 2002 |pmid=11876686 |doi=10.1046/j.1365-2036.2002.01185.x|s2cid=24133545 |doi-access=free }}</ref> 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<!-- works --> on 5-HT<sub>3</sub> receptors in the gut and brain stem.<ref name ="kamm_2001"/>

==Drug design{{anchor|5-HT3 antagonists drug design}}==
Experiments have shown evidence that the ligand-binding site is located at the interface of two adjacent subunits.<ref name= Zhu_2006>{{cite journal |vauthors=Zhu LP, Ye DY, Tang Y |title=Structure-based 3D-QSAR studies on thiazoles as 5-HT3 receptor antagonists |journal=Journal of Molecular Modeling |volume=13 |issue=1 |pages=121–31 |date=January 2007 |pmid=16953442 |doi=10.1007/s00894-006-0131-1|s2cid=30877434 }}</ref> 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).<ref name = "Barnes_2008" /><ref name= Reeves_2002>{{cite journal |vauthors=Reeves DC, Lummis SC |title=The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel (review) |journal=Molecular Membrane Biology |volume=19 |issue=1 |pages=11–26 |year=2002 |pmid=11989819 |doi=10.1080/09687680110110048|s2cid=36985954 |doi-access=free }}</ref> 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 critical [[tryptophan]] ligand binding residue that contributes to a cation-π interaction between the pi [[electron]] density of tryptophan and the primary amine of 5-HT.  Loop C residues have been considered as candidates for the differing [[pharmacology]] of [[rodent]] and [[human]] 5-HT<sub>3</sub> receptors because of their divergence between species.  The most important [[aromatic]] residue within loop C is probably Y234 that lies opposite to the loop B [[tryptophan]] in 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 competitive [[antagonist]] granisetron is located close to W183 forming a cation-pi interaction.<ref name= Duffy_2012>{{cite journal |vauthors=Duffy NH, Lester HA, Dougherty DA |title=Ondansetron and Granisetron Binding Orientation in the 5-HT3 Receptor Determined by Unnatural Amino Acid Mutagenesis |journal=ACS Chemical Biology |volume=7 |issue=10 |pages=1738–45 |year=2007 |doi=10.1021/cb300246j|pmid=22873819 |pmc=3477246 }}</ref>   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.<ref name = "Barnes_2008" />

{| class="wikitable"
|+ Binding affinity of 5-HT<sub>3</sub> receptor antagonist<ref name="Thompson_2006"/>
|-
! 5-HT<sub>3</sub> receptor antagonists
! Binding affinity (K<sub>d</sub>, K<sub>i</sub>, K<sub>50</sub>)
! 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|Pharmacophore scaffold]] ===
[[File:Ondansetron skeletal.svg|class=skin-invert-image|thumb|200px|Fig 1. Ondansetron: First generation 5-HT<sub>3</sub> receptor antagonist]]
[[File:Palonosetron.svg|class=skin-invert-image|thumb|200px|Fig 2. Palonosetron: Second generation 5-HT<sub>3</sub> receptor antagonist]]

Chemical structures of the first generation 5-HT<sub>3</sub> receptor antagonist can be categorized to three main classes<ref name ="Gan_2005"/>
#[[Carbazole]] derivatives (ondansetron)
#[[Indazoles]] (Granisetron)
#[[Indoles]] ([[Tropisetron]] and [[Dolasetron]])

The first-generation 5-HT<sub>3</sub> receptor antagonist (ondansetron, [[dolasetron]], granisetron, and [[tropisetron]]) have been the most important drugs in antiemetic therapy for emetogenic [[chemotherapy]]. They are especially effective in treating acute [[emesis]], occurring in the first 24 hours following [[chemotherapy]].<ref name ="Oo_2005"/>
A newer drug [[palonosetron]] is a pharmacologically distinct and highly selective, second generation 5-HT<sub>3</sub> receptor antagonist.<ref name= Tian_2006>{{cite journal |vauthors=Tian K, Chen H, Tang J, Chen X, Hu Z |title=Enantioseparation of palonosetron hydrochloride by micellar electrokinetic chromatography with sodium cholate as chiral selector |journal=Journal of Chromatography A |volume=1132 |issue=1–2 |pages=333–6 |date=November 2006 |pmid=16999973 |doi=10.1016/j.chroma.2006.08.090}}</ref> [[Palonosetron]] has two [[stereogenic]] centers and exists as four [[stereoisomers]].<ref name="Tian_2006"/>
Palonosetron has longer half-life (40h) and greater receptor binding affinity (>30 fold; when compared to first generation antagonists).<ref name="Oo_2005"/>

=== Pharmacophore ===
[[File:Wikimynd1.jpg|class=skin-invert-image|thumb|400px|right|Fig 3. The 5-HT<sub>3</sub> receptor antagonists pharmacophore (schematic)]]
The [[pharmacophore]] of 5-HT<sub>3</sub>receptors consists of three components: a carbonyl-containing linking moiety,  [[aromatic]]/[[heteroaromatic]] ring, and a basic center.  The [[carbonyl]] group is coplanar to the [[aromatic ring]]. 5-HT<sub>3</sub> receptor antagonists are more likely to bind in their protonated form.<ref name= Hibert_1989>{{cite journal |vauthors=Hibert MF, Hoffmann R, Miller RC, Carr AA |title=Conformation-activity relationship study of 5-HT3 receptor antagonists and a definition of a model for this receptor site |journal=Journal of Medicinal Chemistry |volume=33 |issue=6 |pages=1594–600 |date=June 1990 |pmid=2342053 |doi=10.1021/jm00168a011}}</ref> Docking of a range of antagonists into a homology model of the [[5HT3 receptor|5-HT<sub>3</sub> receptor]] binding site shows a reasonably good agreement with the [[pharmacophore]] model and supports the observed differences between species. Studies of granisetron in the binding pocket revealed that the [[aromatic]] rings 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-HT<sub>3</sub> receptor.<ref name= Thompson_2006>{{cite journal |vauthors=Thompson AJ, Lummis SC |title=5-HT3 Receptors |journal=Current Pharmaceutical Design |volume=12 |issue=28 |pages=3615–30 |year=2006 |pmid=17073663 |pmc=2664614 |doi=10.2174/138161206778522029}}</ref>

=== Structure-activity relationship ===
[[File:Wikimynd3.png|class=skin-invert-image|thumb|Fig 4. The main pharmacophoric elements of the known 5-HT<sub>3</sub> antagonist]]
5-HT<sub>3</sub> receptor antagonists share the same [[pharmacophore]].<ref name="Thompson_2006" /> An aromatic moiety (preferably indole), a linking acyl group capable of [[hydrogen bonding]] interactions, and a basic [[amine]] ([[nitrogen]]) can be regarded as the key [[pharmacophore|pharmacophoric]] elements of the known 5-HT<sub>3</sub>receptor antagonists. There are steric limitations of the [[aromatic]] binding site and although two hydrogen-bonding interactions are possible on the [[heterocyclic]] linking 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 secondary [[amines]] being more potent.<ref name = Swain_1991>{{cite journal |author=Swain CJ |title=Novel 5-HT3 antagonists. Indole oxadiazoles |journal=Journal of Medicinal Chemistry |volume=34 |issue=1 |pages=140–51 |date=January 1991 |pmid=1992112 |doi=10.1021/jm00105a021 |author2=Baker R |author3=Kneen C |display-authors=3 |last4=Moseley |first4=J. |last5=Saunders |first5=J. |last6=Seward |first6=E. M. |last7=Stevenson |first7=G. |last8=Beer |first8=M. |last9=Stanton |first9=J.}}</ref> The 5-HT3 receptor can only accommodate small substituents on the charged amine, a [[methyl]] group being optimal.<ref name ="Thompson_2006"/> 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.<ref name ="Swain_1991"/> The most [[Potent (pharmacology)|potent]] antagonists of 5-HT<sub>3</sub> receptors have a 6-membered [[aromatic]] ring, and they usually have 6,5 [[heterocyclic]] rings.<ref name ="Thompson_2006"/> No correlation has been found between the [[lipophilicity]] of compounds and the 5-HT<sub>3</sub> receptor affinities.<ref name= Cappelli_1996>{{cite journal |author=Cappelli A |title=Molecular structure and dynamics of some potent 5-HT3 receptor antagonists. Insight into the interaction with the receptor |journal=Bioorganic & Medicinal Chemistry |volume=4 |issue=8 |pages=1255–69 |date=August 1996 |pmid=8879547 |doi=10.1016/0968-0896(96)00122-8 |author2=Donati A |author3=Anzini M |display-authors=3 |last4=Vomero |first4=Salvatore |last5=De Benedetti |first5=Pier G. |last6=Menziani |first6=Maria Cristina |last7=Langer |first7=Thierry}}</ref>  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.<ref name ="Swain_1991"/>
[[File:Wikimynd4.png|class=skin-invert-image|thumb|Fig 5. The importance of C5 (R1) and C7 (R2) substitution has been studied]]

[[Structure activity relationship|Structure-activity relationship]] (SAR) studies of [[Ligand gated ion channel|LGIC]] receptor ligands are valuable to investigate their structure and function.  An [[antagonist]]-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, [[hydrophobic]] groove 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 gating [[amino acid]] residues and favor the open conformation of the ion channel because of sterical repulsion.<ref name = Yoshida_2007>{{cite journal |vauthors=Yoshida S, Watanabe T, Sato Y |title=Regulatory molecules for the 5-HT3 receptor ion channel gating system |journal=Bioorganic & Medicinal Chemistry |volume=15 |issue=10 |pages=3515–23 |date=May 2007 |pmid=17391967 |doi=10.1016/j.bmc.2007.02.054}}</ref>

[[File:Wikimynd6.jpg|class=skin-invert-image|thumb|Fig 6. The carbonyl group is completely coplanar with the adjacent aromatic ring]]
Ondansetron is a [[racemate]] but the [[stereochemistry]] of the asymmetric [[carbon]] [[atom]] is not an important factor in the 5-HT<sub>3</sub> receptor interaction.  Annelation of the 1,7-positions of the indole nucleus of ondansetron results in increased affinity for the [[Receptor (biochemistry)|receptor]].<ref name= Wijngaarden_1993>{{cite journal |author=van Wijngaarden I |title=Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives |journal=Journal of Medicinal Chemistry |volume=36 |issue=23 |pages=3693–9 |date=November 1993 |pmid=8246239 |doi=10.1021/jm00075a026 |author2=Hamminga D |author3=van Hes R |display-authors=3 |last4=Standaar |first4=Piet J. |last5=Tipker |first5=Jacobus |last6=Tulp |first6=Martin T. M. |last7=Mol |first7=Frans |last8=Olivier |first8=Berend |last9=De Jonge |first9=Adriaan}}</ref>

A methyl- group appears to be as effective functionally as a chlorine in the R position (see fig. 6).  The [[carbonyl]] group is responsible for a strong interaction with the receptor and contributes significantly to the binding process.  This carbonyl group is completely [[coplanar]] with the adjacent [[aromatic]] ring, indicating that the receptor-bound conformation corresponds to one of the most stable conformations of this group in the flexible compounds.<ref name ="Hibert_1989"/>

==Research==
A small, [[open-label trial]] carried out in 2000 found ondansetron to be useful in treating [[antipsychotic]]-induced [[tardive dyskinesia]] in people with [[schizophrenia]].<ref>{{cite journal |vauthors=Zullino DF, Eap CB, Voirol P |title=Ondansetron for tardive dyskinesia |journal=Am J Psychiatry |volume=158 |issue=4 |pages=657–8 |year=2001 |pmid=11282718 |doi=10.1176/appi.ajp.158.4.657-a}}</ref><ref>{{cite journal |vauthors=Sirota P, Mosheva T, Shabtay H, Giladi N, Korczyn AD |title=Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia |journal=Am J Psychiatry |volume=157 |issue=2 |pages=287–9 |year=2000 |pmid=10671405 |doi=10.1176/appi.ajp.157.2.287}} [http://ajp.psychiatryonline.org/cgi/content/full/157/2/287 Free full text]</ref> 
The study's patients also showed [[statistical significance|significant]] improvement in the disease's symptoms; a later [[double-blind]], [[randomized controlled trial]] also found ondansetron to significantly improve schizophrenia symptoms when used as an adjunct to [[haloperidol]], and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol.<ref>{{cite journal |vauthors=Zhang ZJ, Kang WH, Li Q, Wang XY, Yao SM, Ma AQ |title=Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study |journal=[[Schizophrenia Research]] |volume=88 |issue=1–3 |pages=102–10 |year=2006 |pmid=16959472 |doi=10.1016/j.schres.2006.07.010|s2cid=24911372 }}</ref>

==See also==
*[[Serotonin transporter]]

==References==
{{Reflist|35em}}

{{refbegin}}
*{{cite book |last=Pasricha |first=Pankaj J. |editor=Laurence Brunton |editor2=John Lazo |editor3=Keith Parker |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th |year=2006 |publisher=[[McGraw-Hill]] |location=New York |isbn=978-0-07-142280-2|chapter=Treatment of Disorders of Bowel Motility and Water Flux; Antiemetics; Agents Used in Biliary and Pancreatic Disease |title-link=Goodman & Gilman's The Pharmacological Basis of Therapeutics }}
*{{cite book |last=Hillier |first=Keith |author2=Robert J. Naylor |editor=Clive Page |editor2=Brian Hoffmann |editor3=Michael Curtis |editor4=Michael Walker |title=Integrated Pharmacology |edition=3rd |chapter=Drugs and the Gastrointestinal System|year=2006 |publisher=Mosby |isbn=978-0-323-04080-8}}
{{refend}}

{{Serotonergics}}
{{5-HT3 antagonists}}
{{Drugs for functional gastrointestinal disorders}}
{{Receptor agonists and antagonists}}

{{DEFAULTSORT:5-Ht3 Antagonist}}
[[Category:5-HT3 antagonists]]
[[Category:Antiemetics]]