The 5-HT3 antagonists, informally known as "setrons", are a
class of drugs that act as
receptor antagonists at the
5-HT3 receptor, a subtype of
serotoninreceptor 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-HT3 antagonists are
antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by
cancer chemotherapy and are considered the gold standard for this purpose.[1]
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. They are usually given
intravenously, shortly before administration of the chemotherapeutic agent,[3] although some authors have argued that oral administration may be preferred.[4]
The concomitant administration of a
NK1 receptor antagonist, such as
aprepitant,
significantly increases the efficacy of 5-HT3 antagonists in preventing both acute and delayed CINV.[5]
The 5-HT3 antagonists are also indicated in the prevention and treatment of
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.
Ondansetron was the first 5-HT3 antagonist, developed by
Glaxo around 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 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-HT3 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.[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.
Granisetron was developed around 1988.[14] It is available in the U.S., UK, Australia and other countries.
Clinical trials suggest that it is more effective than other 5-HT3 antagonists in preventing delayed CINV (nausea and vomiting that occur more than 24 hours after the first dose of chemotherapy).[15] It is taken once daily.
Dolasetron was first mentioned in the literature in 1989.[16] It is a
prodrug, and most of its effects are due to its active metabolite, hydrodolasetron, which is formed in the
liver by the
enzymecarbonyl reductase. Dolasetron was approved by the FDA in 1997, and is also administered once daily.
Palonosetron is the newest 5-HT3 antagonist to become available in the U.S. market. It is an
isoquinoline derivative, and is effective in preventing delayed CINV.[17] Palonosetron was approved by the FDA in 2003,[18] initially for
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.[19]
Ramosetron is only available in Japan and certain
Southeast Asian countries as of 2008.[20] It has higher
affinity for the 5-HT3 receptor than the older 5-HT3 antagonists, and maintains its effects over two days; it is therefore
significantly more effective for delayed CINV.[21] In animal studies, ramosetron was also effective against
irritable bowel syndrome-like symptoms.[22]
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.[23]
Certain
prokinetic drugs such as
cisapride,
renzapride and
metoclopramide, although not 5-HT3 antagonists proper, possess some weak antagonist effect at the 5-HT3 receptor.
Galanolactone, a
diterpenoid found in
ginger, is a 5-HT3 antagonist and is believed to at least partially mediate the anti-emetic activity of this plant.[24][25]Mirtazapine is a tetracyclic antidepressant with 5-HT2 and 5-HT3 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.[26] Mirtazapine has also been used in the treatment of the motility disorder
gastroparesis due to its anti-emetic effects.[27]Olanzapine, an
atypical antipsychotic with anti-emetic properties similar to those of mirtazapine, also shows promise in treating chemotherapy-induced nausea and vomiting.[26]
All 5-HT3 antagonists have been associated with
asymptomaticelectrocardiogram changes, such as prolongation of the PT and QTc intervals and certain
arrhythmias.[28] The clinical significance of these side effects is unknown.
Pharmacology
Mechanism of action
The 5-HT3 receptors are present in several critical sites involved in emesis, including
vagalafferents, the
solitary tract nucleus (STN), and the area postrema itself.
Serotonin is released by the
enterochromaffincells of the
small intestine in response to
chemotherapeutic agents and may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. The 5-HT3 receptor antagonists suppress vomiting and nausea by inhibiting serotonin binding to the 5-HT3 receptors. 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.[29] The 5-HT3 antagonists are greatly selective and have little affinity for other receptors, such as
dopamine,
histamine and
muscarinic acetylcholine receptors.[28]
Pharmacokinetics
All 5-HT3 antagonists are well-absorbed and effective after oral administration,[4][28] and all are metabolized in the
liver by various
isoenzymes of the
cytochrome P450 system. They do not, however,
inhibit or
induce these enzymes.[28]
Comparative pharmacology
Despite that the 5-HT3 receptor antagonists share their
mechanism of action, they have different
chemical structures and exhibit differences in affinity for the
receptor, dose response and duration of effect. They are also
metabolized in different ways, that is, different components of the
cytochrome P450 (
CYP) system predominate in the
metabolism of the antagonists.[30]
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.[31]
Comparative pharmacology of 5-HT3 receptor antagonist[29]
The history of the 5-HT3 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
dibenzyline respectively).[33] The 5-HT3 receptor was later found to correspond to the M receptor.[34] In the 1970s, John Fozard found that
metoclopramide and
cocaine were 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-HT3 receptor 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 at
Sandoz identified the potent, selective 5-HT3 receptor antagonist ICS 205-930 from which the first marketed selective 5-HT3 receptor antagonists
ondansetron and
granisetron were 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-HT3 receptor antagonist, named palonosetron, was approved in 2003.[37]
The development of selective 5-HT3 receptor antagonists was a dramatic improvement in the
treatment of 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 acute
emesis with chemotherapy agents with moderate to high emetogenic potential.[38]
Development
5-HT3 receptor antagonists or serotonin
antagonists were first introduced in the early 1990s, and they have become the most widely used antiemetic drugs in
chemotherapy.[29] They have also been proven safe and effective for treatment of
postoperative nausea and vomiting.[30] Serotonin (5-HT) is found widely distributed throughout the
gut and the
central nervous system. In the gut,
5-HT is found mostly in
mucosalenterochromaffincells. Enterochromaffin cells are sensory transducers that release
5-HT to activate
intrinsic (via 5-HT1P and 5-HT4 receptors) and
extrinsic (via 5-HT3 receptors) primary
afferent 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-HT3 receptors in the gut and brain stem.[39]
Drug design
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 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-HT3 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.[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]
The first-generation 5-HT3 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.[38]
A newer drug
palonosetron is a pharmacologically distinct and highly selective, second generation 5-HT3 receptor antagonist.[44]Palonosetron has two
stereogenic centers and exists as four
stereoisomers.[44]
Palonosetron has longer half-life (40h) and greater receptor binding affinity (>30 fold; when compared to first generation antagonists).[38]
Pharmacophore
The
pharmacophore of 5-HT3receptors 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-HT3 receptor antagonists are more likely to bind in their protonated form.[45] Docking of a range of antagonists into a homology model of the
5-HT3 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-HT3 receptor.[43]
Structure-activity relationship
5-HT3 receptor antagonists share the same
pharmacophore.[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. 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.[46] The 5-HT3 receptor can only accommodate small substituents on the charged amine, a
methyl group 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 most
potent antagonists of 5-HT3 receptors have a 6-membered
aromatic ring, and they usually have 6,5
heterocyclic rings.[43] No correlation has been found between the
lipophilicity of compounds and the 5-HT3 receptor 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]
Structure-activity relationship (SAR) studies of
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.[48]
Ondansetron is a
racemate but the
stereochemistry of the asymmetric
carbonatom is not an important factor in the 5-HT3 receptor interaction. Annelation of the 1,7-positions of the indole nucleus of ondansetron results in increased affinity for the
receptor.[49]
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.[45]
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