Current Treatment

6.30.5.1 Prokinetic Agents 6.30.5.1.1 5HT4 receptor agonists

5HT4 receptors are located on the enteric nervous system within the GI tract of humans and a number of animal species. Activation of these receptors with agonists evokes the release of excitatory and inhibitory neurotransmitters, with the net result of increasing motility and orthograde peristalsis in the GI tract. The first 5HT4 receptor agonist prokinetic, metoclopramide (5), was adopted for clinical use before the target receptor had been characterized and the molecular mechanism of action of metoclopramide was disputed. Metoclopramide has moderate affinity and potency at the 5HT4 receptor in vitro and has prokinetic activity in models of gastric emptying. For example, in a rat model metoclopramide increased gastric emptying dose-dependently following oral dosing.6 The mechanism of action of metoclopramide to increase gastric emptying was proposed as the enhancement of acetylcholine release, but this was the subject of controversy. Furthermore, the precise molecular target for metoclopramide remained in doubt, which arose from the complex pharmacology of this molecule. In addition to its activity at 5HT4 receptors, metoclopramide has significant antagonist activity at both 5HT3 and dopamine D2 receptors. All of these activities have been proposed as underpinning the prokinetic activity of metoclopramide. Examination of compounds with 5HT3 receptor antagonist activity in in vitro and in vivo models of intestinal motility including: gastric emptying in the rat and gastric contraction in the dog and the classic in vivo model of 5HT3 receptor blockade, the Bezold-Jarisch reflex in the anesthetized rat, showed that compounds containing benzamide moieties (e.g., metoclopramide, zacopride, and cisapride) were highly active in all models of GI motor function tested, whereas those without this structural motif only increased rat gastric emptying.7 Comparison of the rank orders of potency in the Bezold-Jarisch reflex and the motility models implicated a receptor other than 5HT3 in the promotility effects of the benzamide compounds, with metoclopramide and cisapride subsequently being shown to increase GI motor activity and propulsion via 5HT4 receptor activation.8 Agonism of 5HT4 receptors increases lower esophageal sphincter tone,9 increases esophageal peristalsis,10 and promotes gastric emptying11 in humans all of which might reduce exposure of the lower esophagus to gastric refluxate and so improve symptoms in GERD. In GERD patients, cisapride is superior to placebo in promoting mucosal healing and reducing heartburn.12 Cisapride treatment resulted in healing in 50-70% of patients, underlining the potential of this drug class as stand-alone agents.13

Numerous 5HT4 receptor agonists have been identified and have prokinetic activity in animal models, although few have been tested clinically. Renzapride (6) and zacopride (7) are contemporaries of cisapride and both share its benzamide structural motif. Both are potent agonists at the 5HT4 receptor, but have significant 5HT3 antagonist activity. Both compounds accelerate gastric emptying in animal models. Renzapride reversed drug-induced gastroparesis in dogs14 and zacopride partially reversed the delay in gastric emptying in a rodent model of diabetic gastroparesis.15 In healthy volunteers, renzapride increases lower oesophageal sphincter pressure16 and gastric emptying in patients with diabetic gastroparesis.17 In conscious dogs, renzapride stimulated motility along the entire length of the colon.18 In patients with C-IBS, renzapride accelerated colonic transit, apparently through an effect on the ascending colon, but was without effect on gastric emptying.19 Renzapride is currently under clinical development for the treatment of C-IBS. Mosapride (8) is another 5HT4 receptor partial agonist in clinical use in Asia that has an interesting profile in animal models of gastric and intestinal motility. In conscious dogs, mosapride stimulates contractility in the gastric antrum, but has no effect on the colon at the doses tested.20 In a mouse model of morphine-induced delay of gastric emptying, mosapride effectively reverses drug-induced gastroparesis.21 Mosapride and other 5HT4 receptor agonists relax the esophagus of rats in vivo, as studied using the novel technique of digital sonomicrometry.22 However, the effects of mosapride on the colon are controversial, having only been demonstrated in the guinea pig.23 In humans, mosapride has been shown to increase gastric emptying in healthy volunteers24 and in patients with diabetic gastroparesis.25 In patients with GERD, mosapride has been shown to decrease reflux episodes and to reduce esophageal acid exposure.26 The effects of mosapride on the human colon have not been investigated;

however, in a pilot study in patients with Parkinson's disease, mosapride treatment had some utility in the relief of

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