Blockade of D2 receptors present on enteric neurons and/or those located at the chemoreceptor trigger zone may promote motility. In fact, D2 receptor antagonists such as metoclopramide and domperidone are in use for the treatment of dyspeptic symptoms, despite potential side effects such as hyperprolactinemia and extrapyramidal dystonic reactions .
Itopride 1, which is available on the market in Japan, is a D2 receptor antagonist, which also exhibits acetylcholine esterase inhibition. The compound stimulated GI motility when dosed i.v. to conscious dogs and promoted colonic transit in rats and guinea pigs after oral administration . After 8 weeks treatment in patients with FD, oral itopride t.i.d. was significantly more effective than placebo in reducing self-reported symptom scores including pain and fullness . In a smaller trial in patients with GERD, itopride t.i.d. for 30 days significantly improved acid reflux and symptoms such as heartburn compared to pre-treatment . In both studies, while there was some increase in prolactin levels, no significant adverse events occurred. However, most recent reports indicate that itopride did not meet expectations in clinical phase III studies in FD .
2.2. Serotonin 5-HT4 receptor agonists
Serotonin (5-HT) is considered a key mediator/neurotransmitter in the GI tract. Large amounts of 5-HT are stored in enterochromaffin cells in the gut and released in a highly regulated fashion. Moreover, serotoninergic neurons are present in the enteric nervous system. Of all serotonin receptor subtypes found in the GI tract, both 5-HT3 and 5-HT4 receptors have been investigated most thoroughly. 5-HT4 receptors located on nerve terminals of GI motor- and interneurons facilitate the release of neurotransmitters such as acetylcholine and, thereby, enhance motility. More recent data also suggest a role of 5-HT4 receptors in the triggering of the peristaltic reflex . Hence, agonism at the 5-HT4 receptor is an established pro-kinetic mechanism .
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Mosapride 2 is a selective 5-HT4 receptor agonist, which is marketed in Japan to treat gastric disturbances. While a close analogue of cisapride, mosapride shows no similar cardiac adverse effects. However, the overall pharmacodynamic profile of mosapride appears to be similar to that of cisapride, since the primary debenzylated metabolite of mosapride exhibits 5-HT3 receptor antagonist activity. In GERD patients, mosapride t.i.d. for 7 days showed a significant but small effect on improvement in acid reflux variables and esophagal motor function compared to the pre-treatment period. These effects are comparable to those seen with cisapride . In FD patients, mosapride t.i.d. for 4 weeks provided modest but significant improvements in self-reported symptom scores compared to the pre-treatment period .
ATI-7505 3 is in development for the treatment of reflux disease. This compound, another 5-HT4 receptor agonist, accelerated gastric emptying following dosing of 0.2mg/kg i.v. to fed dogs. ATI-7505 exhibited prokinetic effects in the upper GI tract including small intestine rather than colonic motor activity .
Renzapride 4 is a dual 5-HT4 agonist/5-HT3 antagonist in development for the treatment of IBS-C. A recent mechanistic study demonstrated significantly improved colonic transit rates compared to placebo in patients with IBS-C after treatment for 11-14 days. Interestingly, the acceleration of colonic transit did not lead to any o n o significant effects on bowel function (no improvement or satisfactory relief of symptom) .
Prucalopride 5 is a selective 5-HT4 agonist which when dosed once daily for 4 weeks showed significant improvements compared to placebo in stool softening, decreased straining and time to first stool in patients with chronic constipation, who were refractory to laxatives. However, further development of this compound is on hold due to carcinogenicity issues .
Tegaserod 6 is a 5-HT4 receptor agonist which has been approved by the FDA for IBS-C and chronic idiopathic constipation and is marketed in the US and elsewhere. Tegaserod is rapidly absorbed in man and shows linear pharmacokinet-ics in a 2-12 mg oral dose range, with no significant differences found between healthy volunteers, young or elderly IBS patients . In clinical phase III studies for IBS-C conducted in predominantly female patients, tegaserod b.i.d. at 6mg for 12 weeks compared to placebo demonstrated significant improvements in self-reported symptom scores including abdominal pain, bloating and bowel function. Interestingly, stimulation of 5-HT4 receptors with tegaserod has been shown to attenuate visceral sensitivity (visceral pain response) in both animals and humans. The drug is well tolerated, with transient diarrhea/soft stools being the most frequent adverse event found . Phase III data in patients suffering from idiopathic chronic constipation indicated that tegaserod at 2 or 6mg b.i.d. for 12 weeks significantly increased the number and quality of spontaneous bowel movements, compared to placebo . A recent meta-analysis of all placebo-controlled trials of agents for chronic constipation ranked tegaserod with the osmotic laxative polyethylene glycol as the only two modalities for which there was a good level of evidence to recommend their use in this disorder .
5-HT3 receptors are located on vagal afferents and myenteric neurons. They are involved in both contractile and secretory responses and can trigger sensory signals through the vagus nerve. 5-HT3 receptor antagonists are well known to attenuate chemotherapy-induced nausea and emesis through the inhibition of vagal signaling and to inhibit intestinal motility and secretion. In agreement with these activities, alosetron (5-HT3 antagonist) has been developed for the treatment of IBS with diarrhea and conversely, a 5-HT3 agonist might be expected to increase motility. In line with this hypothesis, a single 4mg dose of the 5-HT3 receptor agonist, pumo-setrag 7, significantly accelerated small intestinal transit compared to placebo in healthy volunteers. However, significant side effects of nausea, flushing and itching, all associated with systemic activation of 5-HT3 receptors were also observed . In a small exploratory study of patients with idiopathic constipation, pumosetrag given 0.5 mg once daily for 2 weeks showed significant improvement in bowel mo-tility after a 1 week placebo run-in; the systemic side effects seen in the previous study were not noted at this lower dose .
Chlolecystokinin (CCK) is released from endocrine cells in the duodenal and jejunal mucosa in response to certain food components and promotes inhibition of gastric emptying, among other effects. These effects of CCK are mediated through the CCKa (or CCK1) receptor, blockade of which represents an approach to stimulate gut motility. In line with this, symptom improvements with the CCKa antagonist, loxiglumide, have been demonstrated in FD patients . The active single enantiomer of loxiglumide, dexloxiglumide 8 t.i.d. for 7 days significantly accelerated gastric emptying in patients with IBS-C compared to placebo. However, overall colonic transit was unaffected and no significant relief of global IBS symptoms or overall bowel function were observed . Recent information indicates that dexloxiglumide failed in clinical phase III studies in patients suffering from
2.5. Motilin receptor agonists
Motilin is a 22 amino acid polypeptide, which primarily stimulates antral contractions and thus promotes gastric emptying. This effect is mediated through the motilin receptor, which is expressed throughout the gut. Many synthetic motilin agonists are derived from the macrolide antibiotic, erythromycin, which exhibits gastric motor stimulation effects due to motilin receptor activation, in addition to its antibiotic activity . These compounds, such as alemcinal (ABT-229) 9, exhibit improved potency at the motilin receptor and minimal antibiotic activity. However, 9 failed to show efficacy in relieving symptoms of GERD compared to placebo when dosed up to 10 mg t.i.d. for 8 weeks . ABT-229 and another macrolide, KC11458, showed no improvement over placebo in affecting gastric emptying rates in patients with diabetic gastroparesis [23,24]. One explanation for the lack of efficacy with these compounds may be rapid induction of tachyphylaxis. Receptor trafficking studies using confocal microscopy have shown that the extent of motilin receptor downregulation varied from compound to compound [25,26], leaving open the possibility of selecting a clinically useful compound by early screening for tachylphylaxis effects. A recent patent highlights such an approach, identifying macrolides with reduced potential to induce tachyphylaxis compared with 9 or erythromycin, using an in vitro rabbit duodenal strip model .
In an alternative approach, a non-macrolide 10 optimized from a high-throughput screen for motilin agonism, was reported to show similar potency and reduced tachyphylactic potential compared to 9 .
Very recently, atilmotin, a peptide analogue of the 1-14 amino acid fragment of motilin, has been reported, which remains a potent and selective motilin agonist. When dosed as a single i.v. bolus after three meals in healthy volunteers, atilmotin showed a relatively short-lived increase in gastric emptying rate compared to placebo, which may be related to the short half-life of the compound. However, the short half-life may also contribute to reduced tachyphylaxis effects of atilmotin .
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