Prucalopride (10) is a 5HT4 agonist whose activity in the lower GI tract has attracted attention. In conscious dogs, prucalopride stimulates motor activity in the proximal colon, although distal colon activity is inhibited34 and in healthy human volunteers, prucalopride decreases colonic transit time.35 This prokinetic effect has also been seen in patients with constipation, where prucalopride increased GI transit in the small and large intestine as well as increasing gastric emptying.36 Prucalopride also provides symptomatic improvement in patients with constipation.37 SK-951 (11) is a benzofuran derivative like prucalopride and is a potent agonist at the 5HT4 receptor, although the compound also has high affinity at 5HT3 receptors. SK-951 increases gastric emptying in rats and dogs, and in a canine model of postvagotomy gastroparesis.38 In a further study, the ability of SK-951 to increase delayed gastric emptying in a canine model of diabetic gastroparesis has been demonstrated.39

10 Prucalopride 11 SK-951

Recently, several compounds containing the benzamide structural motifs have been described. These are novel 5HT4 receptor agonists but often combine this functionality with additional pharmacological activity. Such agents include KDR-5169 (12), TKS-159 (13), and YM-53389 (14). KDR-5169 combines 5HT4 agonism with dopamine D2 receptor antagonism. It increases GI transit in three different rat models of gastroparesis40 and in conscious dogs, not only stimulates fasting motility in the small intestine but also stimulates postprandial small intestinal motility that had been inhibited by previous administration of L-DOPA. YM-53389 is a 5HT4 receptor agonist that is highly selective for 5HT4 receptors compared to 5HT3 receptors. In mice, YM-53389 selectively increases colonic propulsion as whole gut transit time was increased by this NCE without any effect on upper gut motor function. TKS-159 appears to be a selective and specific 5HT4 agonist that increases gastric motor activity in the whole stomach and in the Heidenhain pouch in conscious dog.42 Novel 5HT4 agonists that do not contain the benzamide motif have also been described. ML-10302 (15) has been shown to stimulate motor activity in the small and large intestine of conscious dogs.43 BIMU1 (16) represents another structural class of 5HT4 agonist, the benzimidazolones. This agent has agonist activity at 5HT4 receptors and antagonist activity at 5HT3 receptors. BIMU1 stimulates motility in the Heidenhain pouch dog and also increases the gastric emptying of liquids in a fistula dog model.44 SL-65.0155 (17) has been confirmed pharmacologically as a 5HT4 receptor agonist, although to date its effects on GI motility have not yet been described.45 Dopamine (DA) D2 receptor antagonists

Unquestionably, metoclopramide has antagonist activity at dopamine (DA) D2 receptors; however, its lack of receptor selectivity makes it difficult to categorize its prokinetic effects as resulting solely, or even predominantly, from DA receptor antagonism. The only selective DA receptor antagonist that has been established in clinical practice as a prokinetic agent is domperidone (18). It is differentiated from other DA receptor antagonists, developed for the treatment of schizophrenia, in only poorly crossing the blood-brain barrier, making the dystonic reactions that associated with metoclopramide use a rare occurrence. The precise mechanism through which domperidone increases GI motility remains unclear. Experiments in isolated gastric tissues suggest a potential explanation in that domperidone inhibits an ongoing inhibition of acetylcholine (ACh)-mediated excitatory enteric neurotransmission mediated via DA release.46 In rat, domperidone is effective at stimulating gastric motor function and gastric emptying that has first been inhibited with a DA receptor agonist.38'47 In conscious dogs, domperidone stimulates gastric motility48 increasing gastric emptying, although this effect appears limited to the emptying of liquids.49 The first human studies of the effects of domperidone on gastric emptying pre-date modern measurement techniques. Nonetheless, these pioneer studies clearly demonstrated a prokinetic effect of domperidone either when given alone or when given to reverse the gastroparesis evoked by DA receptor agonists like apomorphine. More recent studies have shown that domperidone accelerates gastric emptying in subjects with gastroparesis,50 although data concerning the effects on basal gastric emptying rates in healthy volunteers are scarce. Following demonstration of the prokinetic effects of domperidone in patients with diabetic gastropathy,51 this agent has become established as a treatment for patients with diabetic gastroparesis, where treatment can increase slowed gastric emptying and reduce symptoms.

The effects of domperidone on intestinal motility and transit have also been studied. In rats, DA antagonists, including domperidone, increase small intestinal transit.52 Similarly, domperidone accelerates small intestinal transit when previously slowed with morphine.21 The effects of domperidone on human GI motor function is more complex. In healthy volunteers, domperidone appears to prolong orocecal transit time,53 while earlier studies suggested a modest acceleration in intestinal transit.54 Another DA receptor antagonist, levosulpiride (19), increases gastric emptying of both liquid and mixed meals in patients with functional dyspepsia55 and diabetic gastroparesis.56 Some degree of symptomatic improvement can be obtained in dyspeptic patients with gastroparesis following treatment with levosulpiride.57

Itopride is a DA D2 receptor antagonist activity with AChase activity, approved for the treatment of gastric motor disorders in Japan. In conscious dogs, itopride (and its hydrochloride salt, HSR-803, 20) enhances gastric contractility induced by ACh, reverses the inhibition of gastric motility evoked by DA, and as a single agent, enhances postprandial gastric motility.48,58 HSR-803 also stimulates gastric emptying and reverses drug-induced gastroparesis in dogs and rats, increases small intestinal motility in mice, and reverses drug-induced ileus. Itopride also increases motility all along the dog intestine.60 Itopride reduces esophageal acid exposure in patients with GERD, an observation consistent with a prokinetic effect.61

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