Reactome | HTR3A antagonists bind HTR3A pentamer

HTR3A antagonists bind HTR3A pentamer

Stable Identifier

R-HSA-9648949

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

ReviewStatus

5/5

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5-hydroxytryptamine receptors 3A (HTR3As, 5-HT3) are present in several critical sites in the CNS involved in emesis and are involved in the integration of the vomiting reflex, pain processing, anxiety control and the reward system. Serotonin (5HT) is released by enterochromaffin cells of the small intestine in response to chemotherapeutic agents which may stimulate vagal afferents (via HTR3A receptors) to initiate the vomiting reflex. 5-HT3 antagonist drugs suppress vomiting and nausea by inhibiting serotonin binding to HTR3A receptors (Tyers & Freeman 1992). 5-HT3 antagonists are widely used for relieving chemotherapy-induced vomiting (Gilmore et al. 2018) as well as radiotherapy-induced and post-operative nausea and vomiting.

5-HT3 antagonists are informally known as "setrons" and are a class of drugs that act as receptor antagonists at the HTR3A receptor. With the exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. 5-HT3 antagonists, although sharing the same mechanism of action, have different chemical structures which lends itself to different affinities for the receptor, dose response, duration of action and different metabolic routes via the cytochrome P450 system. Due to these differences, patients resistant to one antagonist may respond well to another (Gan 2005).

Ondansetron (brand name Zofran) was the first 5-HT3 antagonist, developed by Glaxo in 1984 and approved by the U.S. FDA in 1991 (Griddine & Bush 2019). It is also available in several other countries, including the UK, Ireland, Australia, Canada, France and Brazil. Ondansetron is used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery (Markham & Sorkin 1993) and is also useful in gastroenteritis therapy (Schnadower et al. 2015). Granisetron (trade name Kytril) is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. The drug was approved in the United Kingdom in 1991 and in the United States in 1994. Granisetron is metabolized slowly by the liver, giving it a longer than average half-life (Hsu 2010).

Approved in 2003 by the FDA, palonosetron (trade name Aloxi) is a second generation 5-HT3 receptor antagonist. Unlike the first generation 5-HT3 receptor antagonists, palonosetron demonstrates efficacy in preventing both acute and delayed emesis (Navari 2014). Tropisetron (trade name Navoban) is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy (Lee et al. 1993). It was approved for medical use in 1992 in Europe, Australia, New Zealand, Japan, South Korea and the Philippines but is not available in the U.S.

Ramosetron is a serotonin 5-HT3 receptor antagonist for the treatment of nausea and vomiting (Rabasseda 2002) and for a treatment of diarrhea-predominant irritable bowel syndrome (Hirata et al. 2007, Min & Rhee 2015). It is only licensed for use in Japan and selected Southeast Asian countries and in India. Alosetron (brand name Lotronex) has an antagonist action on the 5-HT3 receptors of the enteric nervous system of the GI tract. It is not classified or approved as an antiemetic, instead, it is used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only (Lacy et al. 2018). It was withdrawn from the market in 2000 due to serious life-threatening gastrointestinal adverse effects (Camilleri et al. 2001), but was reintroduced in 2002 with restricted availability and use (Lucak 2010).

Cilansetron is the first 5-HT3 antagonist specifically designed for IBS that is effective in men as well as women (Olden & Crowell 2005, Zheng et al. 2017). The drug is not available in the U.S. but the manufacturer, Solvay, is in discussion with the MHRA (UK) and EU regulators. Azasetron is an antiemetic which acts as a 5-HT3 receptor antagonist used in the management of nausea and vomiting induced by cancer chemotherapy (Endo et al. 2012). It is approved for marketing in Japan under the trade name Serotone.

Literature References

PubMed ID	Title	Journal	Year
7691500	Ondansetron. An update of its therapeutic use in chemotherapy-induced and postoperative nausea and vomiting Markham, A, Sorkin, EM	Drugs	1993
1387926	Mechanism of the anti-emetic activity of 5-HT3 receptor antagonists Tyers, MB, Freeman, AJ	Oncology	1992
29774051	Alosetron use in clinical practice: significant improvement in irritable bowel syndrome symptoms evaluated using the US Food and Drug Administration composite endpoint Lacy, BE, Nicandro, JP, Chuang, E, Earnest, DL	Therap Adv Gastroenterol	2018
21180598	Optimizing outcomes with alosetron hydrochloride in severe diarrhea-predominant irritable bowel syndrome Lucak, SL	Therap Adv Gastroenterol	2010
17652911	Evaluation of the pharmacological profile of ramosetron, a novel therapeutic agent for irritable bowel syndrome Hirata, T, Keto, Y, Funatsu, T, Akuzawa, S, Sasamata, M	J. Pharmacol. Sci.	2007
7507039	Tropisetron. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic Lee, CR, Plosker, GL, McTavish, D	Drugs	1993
20844345	A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics Hsu, ES	Am J Ther	2010
29763014	Ondansetron Griddine, A, Bush, JS		2019
25949526	The clinical potential of ramosetron in the treatment of irritable bowel syndrome with diarrhea (IBS-D) Min, YW, Rhee, PL	Therap Adv Gastroenterol	2015
16389408	Cilansetron Olden, KW, Crowell, MD	Drugs Today	2005
28291778	Efficacy and safety of 5-hydroxytryptamine 3 receptor antagonists in irritable bowel syndrome: A systematic review and meta-analysis of randomized controlled trials Zheng, Y, Yu, T, Tang, Y, Xiong, W, Shen, X, Jiang, L, Lin, L	PLoS ONE	2017
22993341	A randomized controlled non-inferiority study comparing the antiemetic effect between intravenous granisetron and oral azasetron based on estimated 5-HT3 receptor occupancy Endo, J, Iihara, H, Yamada, M, Yanase, K, Kamiya, F, Ito, F, Funaguchi, N, Ohno, Y, Minatoguchi, S, Itoh, Y	Anticancer Res.	2012
25323946	Palonosetron for the treatment of chemotherapy-induced nausea and vomiting Navari, RM	Expert Opin Pharmacother	2014
11485506	A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome Camilleri, M, Chey, WY, Mayer, EA, Northcutt, AR, Heath, A, Dukes, GE, McSorley, D, Mangel, AM	Arch. Intern. Med.	2001
25333367	Ondansetron and probiotics in the management of pediatric acute gastroenteritis in developed countries Schnadower, D, Finkelstein, Y, Freedman, SB	Curr. Opin. Gastroenterol.	2015
12532186	Ramosetron, a 5-HT3 receptor antagonist for the control of nausea and vomiting Rabasseda, X	Drugs Today	2002