The 5-HT₃ antagonists, informally known as "setrons", are a class of drugs that act as

receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...

s at the 5-HT₃ receptor, a subtype of

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

found in terminals of the

vagus nerve The vagus nerve, also known as the tenth cranial nerve (CN X), plays a crucial role in the autonomic nervous system, which is responsible for regulating involuntary functions within the human body. This nerve carries both sensory and motor fibe ...

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 Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...

, all 5-HT₃ antagonists are

antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...

s, 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. The 5-HT₃ antagonists may be identified by the suffix -setron, and are classified under code A04AA of the 's

Anatomical Therapeutic Chemical Classification System The Anatomical Therapeutic Chemical (ATC) Classification System is a drug classification system that classifies the active ingredients of drugs according to the organ or system on which they act and their therapeutic, pharmacological and chemi ...

Medical uses

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 Cisplatin is a chemical compound with chemical formula, formula ''cis''-. It is a coordination complex of platinum that is used as a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, c ...

; when used for this purpose, they may be given alone or, more frequently, with a

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

, usually dexamethasone. They are usually given

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

, shortly before administration of the chemotherapeutic agent, although some authors have argued that oral administration may be preferred.Free full text with registration at Medscape
/ref> 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. 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. Current evidence suggests that 5-HT₃ antagonists are ineffective in controlling

motion sickness Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include ...

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

Available agents

Ondansetron Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by chemotherapy, radiation therapy, migraines, or surgery. It is also effective for treating gastroenteritis. It can be giv ...

was the first 5-HT₃ antagonist, developed by Glaxo around 1984. Its efficacy was first established in 1987, in animal models, and it was extensively studied over the following years. Ondansetron was approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

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 A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

in the United States. Ondansetron may be given several times daily, depending on the severity of symptoms. * Tropisetron was also first described in 1984. 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. It is available in the U.S., UK, Australia and other countries.

Clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s 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). It is taken once daily. * Dolasetron was first mentioned in the literature in 1989. It is a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

, and most of its effects are due to its active metabolite, ''hydrodolasetron'', which is formed in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

by the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

carbonyl 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 Isoquinoline is an individual chemical specimen - a heterocyclic aromatic organic compound - as well as the name of a family of many thousands of natural plant alkaloids, any one of which might be referred to as "an isoquinoline". It is a struc ...

derivative, and is effective in preventing delayed CINV. Palonosetron was approved by the FDA in 2003, 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. * Ramosetron is only available in Japan and certain

Southeast Asia Southeast Asia is the geographical United Nations geoscheme for Asia#South-eastern Asia, southeastern region of Asia, consisting of the regions that are situated south of China, east of the Indian subcontinent, and northwest of the Mainland Au ...

n countries as of 2008. It has higher

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

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. In animal studies, ramosetron was also effective against

-like symptoms. 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. Certain prokinetic drugs such as cisapride, renzapride and

metoclopramide Metoclopramide is a medication used to treat nausea, vomiting, gastroparesis, and gastroesophageal reflux disease. It is also used to treat migraine headaches. Common side effects include feeling tired, diarrhea, akathisia, and tardive dyski ...

, although not 5-HT₃ antagonists proper, possess some weak antagonist effect at the 5-HT₃ receptor. Galanolactone, a diterpenoid found in

ginger Ginger (''Zingiber officinale'') is a flowering plant whose rhizome, ginger root or ginger, is widely used as a spice and a folk medicine. It is an herbaceous perennial that grows annual pseudostems (false stems made of the rolled bases of l ...

, is a 5-HT₃ antagonist and is believed to at least partially mediate the anti-emetic activity of this plant.

Mirtazapine Mirtazapine, sold under the brand name Remeron among others, is an atypical antidepressant, atypical tetracyclic antidepressant, and as such is used primarily to treat Depression (mood), depression. Its effects may take up to four weeks but ca ...

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. Mirtazapine has also been used in the treatment of the motility disorder

gastroparesis Gastroparesis (gastro- from Ancient Greek – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis") is a medical disorder of ineffective neuromuscular contractions (peristalsis) of the stomach, resulting in food and l ...

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

Adverse effects

There are few

side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

related to the use of 5-HT₃ antagonists; the most common are

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

, and

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

. Unlike

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides ...

s 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. All 5-HT₃ antagonists have been associated with

asymptomatic Asymptomatic (or clinically silent) is an adjective categorising the medical conditions (i.e., injuries or diseases) that patients carry but without experiencing their symptoms, despite an explicit diagnosis (e.g., a positive medical test). P ...

electrocardiogram changes, such as prolongation of the PT and QTc intervals and certain

arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...

s. 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

vagal The vagus nerve, also known as the tenth cranial nerve (CN X), plays a crucial role in the autonomic nervous system, which is responsible for regulating involuntary functions within the human body. This nerve carries both sensory and motor fibe ...

afferents, the solitary tract nucleus (STN), and the area postrema itself.

Serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

is released by the enterochromaffin cells of the

small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...

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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

( 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. The 5-HT₃ antagonists are greatly selective and have little affinity for other receptors, such as

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

and

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

Pharmacokinetics

All 5-HT₃ antagonists are well-absorbed and effective after oral administration, and all are metabolized in the

by various

isoenzyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...

s of the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

system. They do not, however, inhibit or induce these enzymes.

Comparative pharmacology

Despite that the 5-HT₃ receptor antagonists share their

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

, they have different

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

s and exhibit differences in affinity for the

, dose response and duration of effect. They are also metabolized in different ways, that is, different components of the

( CYP) system predominate in the

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of the antagonists. Because of this, patients who are resistant to one

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.alleles An allele is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule. Alleles can differ at a single position through single nucleotide polymorphisms (SNP), but they can also have insertions and deletions ...

and the number of vomiting episodes by patients who receive treatment with

and ondansetron or tropisetron. Patients with multiple alleles tend to be unresponsive to the

drug and vice versa.

History

The history of the 5-HT₃ receptor antagonists began in 1957, when John Gaddum and Zuleika P. Picarelli at the

University of Edinburgh The University of Edinburgh (, ; abbreviated as ''Edin.'' in Post-nominal letters, post-nominals) is a Public university, public research university based in Edinburgh, Scotland. Founded by the City of Edinburgh Council, town council under th ...

proposed the existence of two serotonin receptor subtypes, the ''M'' and ''D'' receptors (thus named because their function could be blocked by

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

and dibenzyline respectively). The 5-HT₃ receptor was later found to correspond to the M receptor. In the 1970s, John Fozard found that

and

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

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. The antiemetic effects of metoclopramide were found to be partially because of its serotonin antagonism. 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 Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by chemotherapy, radiation therapy, migraines, or surgery. It is also effective for treating gastroenteritis. It can be giv ...

and granisetron were developed, and approved in 1991 and 1993 respectively. Several compounds related to MDL 72222 were synthesized which eventually resulted in approval of tropisetron in 1994 and dolasetron in 1997. A new and improved 5-HT₃ receptor antagonist, named palonosetron, was approved in 2003. The development of selective 5-HT₃ receptor antagonists was a dramatic improvement in the treatment of nausea and vomiting. 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.

Development

5-HT₃ receptor antagonists or serotonin

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

. They have also been proven safe and effective for treatment of postoperative nausea and vomiting. Serotonin (5-HT) is found widely distributed throughout the gut and the

. In the gut, 5-HT is found mostly in mucosal enterochromaffin cells. Enterochromaffin cells are sensory transducers that release 5-HT to activate

intrinsic In science and engineering, an intrinsic property is a property of a specified subject that exists itself or within the subject. An extrinsic property is not essential or inherent to the subject that is being characterized. For example, mass i ...

(via 5-HT1P and 5-HT₄ receptors) and extrinsic (via 5-HT₃ receptors) primary afferent nerves. 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.

Drug design

Experiments have shown evidence that the ligand-binding site is located at the interface of two adjacent subunits. 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). 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 Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

ligand binding residue that contributes to a cation-π interaction between the pi

electron The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...

density of tryptophan and the primary amine of 5-HT. Loop C residues have been considered as candidates for the differing

pharmacology Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur betwee ...

rodent Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...

and

human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

5-HT₃ receptors because of their divergence between species. The most important

aromatic In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated system, conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugati ...

residue within loop C is probably Y234 that lies opposite to the loop B

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 An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.

Pharmacophore scaffold

Chemical structures of the first generation 5-HT₃ receptor antagonist can be categorized to three main classes # Carbazole derivatives (ondansetron) # Indazoles (Granisetron) #

Indoles Indole is an organic compound with the formula . Indole is classified as an aromatic Heterocyclic compound, heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are d ...

( Tropisetron and Dolasetron) The first-generation 5-HT₃ receptor antagonist (ondansetron, dolasetron, granisetron, and tropisetron) have been the most important drugs in antiemetic therapy for emetogenic

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

. They are especially effective in treating acute emesis, occurring in the first 24 hours following

. A newer drug palonosetron is a pharmacologically distinct and highly selective, second generation 5-HT₃ receptor antagonist. Palonosetron has two stereogenic centers and exists as four stereoisomers. Palonosetron has longer half-life (40h) and greater receptor binding affinity (>30 fold; when compared to first generation antagonists).

Pharmacophore

The pharmacophore of 5-HT₃receptors consists of three components: a carbonyl-containing linking moiety,

/ heteroaromatic ring, and a basic center. The

carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...

group is coplanar to the aromatic ring. 5-HT₃ receptor antagonists are more likely to bind in their protonated form. 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

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.

Structure-activity relationship

5-HT₃ receptor antagonists share the same pharmacophore. An aromatic moiety (preferably indole), a linking acyl group capable of

hydrogen bonding In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

interactions, and a basic

amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

(

nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...

) can be regarded as the key pharmacophoric elements of the known 5-HT₃receptor antagonists. There are steric limitations of the

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. The 5-HT3 receptor can only accommodate small substituents on the charged amine, a

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...

group being optimal. 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. The most potent antagonists of 5-HT₃ receptors have a 6-membered

ring, and they usually have 6,5 heterocyclic rings. No correlation has been found between the

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are called lipophilic (translated ...

of compounds and the 5-HT₃ receptor affinities. 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. Wikimynd4

Structure-activity relationship (SAR) studies of LGIC receptor ligands are valuable to investigate their structure and function. An

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

residues and favor the open conformation of the ion channel because of sterical repulsion. Wikimynd6

Ondansetron is a

racemate In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

but the

stereochemistry Stereochemistry, a subdiscipline of chemistry, studies the spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoisomers, which are defined ...

of the asymmetric

carbon Carbon () is a chemical element; it has chemical symbol, symbol C and atomic number 6. It is nonmetallic and tetravalence, tetravalent—meaning that its atoms are able to form up to four covalent bonds due to its valence shell exhibiting 4 ...

atom Atoms are the basic particles of the chemical elements. An atom consists of a atomic nucleus, nucleus of protons and generally neutrons, surrounded by an electromagnetically bound swarm of electrons. The chemical elements are distinguished fr ...

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

. A methyl- group appears to be as effective functionally as a chlorine in the R position (see fig. 6). The

group is responsible for a strong interaction with the receptor and contributes significantly to the binding process. This carbonyl group is completely

coplanar In geometry, a set of points in space are coplanar if there exists a geometric plane that contains them all. For example, three points are always coplanar, and if the points are distinct and non-collinear, the plane they determine is unique. How ...

with the adjacent

ring, indicating that the receptor-bound conformation corresponds to one of the most stable conformations of this group in the flexible compounds.

Research

A small,

open-label trial An open-label trial, or open trial, is a type of clinical trial in which information is not withheld from trial participants. In particular, both the researchers and participants know which treatment is being administered. This contrasts with a d ...

carried out in 2000 found ondansetron to be useful in treating

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

-induced tardive dyskinesia in people with

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. The study's patients also showed significant improvement in the disease's symptoms; a later

double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

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.

References

* * {{DEFAULTSORT:5-Ht3 Antagonist 5-HT3 antagonists Antiemetics