Agent |
Action |
GI condition |
Status |
5-HT3 receptor antagonists |
MKC-733[41] (substituted benzamide) |
Delays liquid gastric emptying in association with relaxation of the proximal stomach, stimulates fasting antroduodenal migrating motor complex activity and accelerates small intestinal transit |
Not yet determined |
Under investigation |
5-HT4 receptor agonists |
Prucalopride[42] (benzofuran derivative) |
Prokinetic: stimulates emptying of the stomach and the ascending colon and increases the rate of small and large bowel transit, potentially through the stimulation of high amplitude-propagating contractions and segmental contractions |
IBS with constipation |
Studies on hold (concerns about intestinal carcinogenicity and potential cardiac events) |
Tegaserod[39] (aminoguanidine indole) |
Prokinetic: stimulates 5-HT4 receptors, which are G protein-coupled receptors, and triggers release of additional neurotransmitters, including acetylcholine and calcitonin gene-related peptide, from sensory neurones leading to enhanced GI motility and intestinal secretion and to reduced visceral sensitivity |
IBS with constipation Chronic idiopathic constipation |
Approved by FDA for women with IBS-C men and women <65 with chronic idiopathic constipation |
5-HT3 receptor antagonists (these agents are contraindicated in patients with constipation) |
Alosetron[47] (methylimidazole analogue) |
Activates 5-HT3 receptors, which are ligand-gated cation-channels, resulting in neuronal depolarization that affects the regulation of visceral pain (reduces), colonic transit (slows) and small intestinal absorption (enhances) |
IBS with diarrhoea |
Approved by FDA for women with severe IBS-D for whom treatment with conventional agents has failed under restricted conditions of use, which include a risk management programme, a prescribing programme and a revised indication (above) |
Cilansetron[43] (methylimidazole analogue) |
IBS with diarrhoea |
'Not-approvable' action letter from FDA in March 2005 (more data needed) |
Ondansetron[48] (aminoimidazole carboxamide) |
Antiemetic: centrally acting agents that prevent serotonin from initiating afferent transmission to the CNS through vagal and spinal sympathetic nerves; may also block serotonin stimulation at the chemoreceptor trigger zone and other CNS structures |
CINV PONV RINV |
Approved by FDA for CINV PONV RINV |
Granisetron[49] (aminoimidazole carboxamide) |
Approved by FDA for CINV RINV |
Dolasetron[50] (aminoimidazole carboxamide) |
Approved by FDA for CINV RINV |
Ramosetron[51] (thiazole monofumarate) |
Not approved by FDA |
Palonosetron[52] (isoquinoline) |
Approved by FDA for delayed emesis for patients receiving moderate emetogenic chemotherapy |
5-HT3 receptor antagonist/5-HT4 receptor agonists |
Cisapride (substituted piperidyl benzamide derivative) |
Prokinetic with dual mechanism of action |
Heartburn/GERD Gastroparesis IBS with constipation Constipation |
Withdrawn from market [arrhythmogenic potential (QT internal prolongation)] Available in the United States only through a limited-access programme developed by Janssen Pharmaceutica and the FDA |
5-HT3 receptor antagonist activity |
Antiemetic activity |
Accelerates gastric emptying in some species |
5-HT3 receptor antagonist activity |
Prokinetic activity: enhances the release of acetylcholine from the postganglionic nerve endings of the myenteric plexus, resulting in increased motility in the GI tract by full agonist activity at 5-HT4 receptors |
Mosapride[44,45] (substituted benzamide) |
Prokinetic: facilitates acetylcholine release from enteric cholinergic neurones of the myenteric plexus through stimulation of 5-HT4 receptors, thereby increasing gastric emptying, stimulating gastric motor activity and increasing electrically evoked contractions |
Non-ulcer dyspepsia Gastroparesis Gastric stasis Gastro-oesophageal reflux disease Constipation in Parkinson's disease |
Not approved by FDA |
Renzapride[46] (substituted benzamide) |
Prokinetic: does not alter gastric emptying or small bowel transit but does accelerate colonic transit and ascending colon emptying |
IBS with constipation |
Under investigation (phase III trials) |
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