5-HT3 antagonists are most effective in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV), especially that caused by highly emetogenic drugs such as cisplatin; when used for this purpose, they may be given alone or, more frequently, with a glucocorticoid, usually dexamethasone.

[6][7][8] A randomized, placebo-controlled trial of ondansetron to treat motion sickness in air ambulance personnel showed subjective improvement, but it was not statistically significant.

[9] Alosetron and cilansetron—the latter was developed by 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Alosetron was withdrawn from the U.S. market in 2000 due to unacceptably frequent severe side effects, including ischemic colitis, and is only available through a restrictive program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.

[27] Olanzapine, an atypical antipsychotic with anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.

[28] Unlike antihistamines with antiemetic properties such as cyclizine, 5-HT3 antagonists do not produce sedation, nor do they cause extrapyramidal effects, as phenothiazines (such as prochlorperazine) sometimes do.

The 5-HT3 receptors are present in several critical sites involved in emesis, including vagal afferents, the solitary tract nucleus (STN), and the area postrema itself.

Serotonin is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex.

The highest concentration of 5-HT3 receptors in the central nervous system (CNS) are found in the STN and chemoreceptor trigger zone (CTZ), and 5-HT3 antagonists may also suppress vomiting and nausea by acting at these sites.

[30] 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.

[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.

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.

[43] 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 pharmacophoric elements of the known 5-HT3receptor 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.

[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.

[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.

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.

[45] A small, open-label trial carried out in 2000 found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia.

[50][51] The study's patients also showed 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.