| 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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