5-HT4 agonists

Incomplete conversion was observed at lower temperatures and significant amounts of undesired decomposition products were obtained at temperatures in excess of 150 °C. These processes were applied to the synthesis of biologically important amine-containing compounds such as the seratonin 5-HT4 agonist SC-53116. 

From the indole carbazimidamides investigated, tegaserod (R5 = OMe, R9 = n-pentyl), a potent partial 5-HT4 agonist, was selected for clinical development for the treatment of functional motility disorders based on its overall in vitro and in vivo profile. 

While the 5-HT3 receptor is the most important in control of nausea and vomiting, others are also involved. 5-HT4 agonists have prokinetic properties in nauseated patients with gastroparesis and functional dyspepsia. The 5-HTlD-receptor agonists, such as sumatripan, are used in treatment of migraine and reduce emesis both in this condition and also in the cyclic vomiting syndrome, most likely via action on CNS sites. 

Cisapride, a 5-HT4 agonist, was used in the treatment of gastroesophageal reflux and motility disorders. Because of toxicity, it is now available only for compassionate use in the USA. Tegaserod, a 5-HT4 partial agonist, is used for irritable bowel syndrome with constipation. These drugs are discussed in Chapter 62. 

HT4 agonists enhance the release of acetylcholine in several peripheral tissues and several brain areas (Table 4). 5-HT4 antagonists counteract the effect but, in the studies published so far, caused no change when given alone. The co-location of facilitatory 5-HT4 and inhibitory 5-HTi receptors on hippocampal cholinergic terminals is reminiscent of the co-location of Di and D2 receptors on, for example, GABAergic terminals (Section 2.7). In contrast to the two dopamine receptors,... 

Category 5-HT4 agonist Serotonin type 4 receptor agonist... 

A comparison of various aza-adamantyl containing benzamides in the ratTMM 5-HT4 agonist assay... 

Table 10 illustrates the structures of two of these antagonists. Notably, the amide (11), SC-53606, is ten-fold more potent in the ratTMM assay than the corresponding ester (12) compare pA2 values of 8.13 and 7.0, respectively. We have recently reported that SC-53606 exhibits similar pA2 values in this preparation regardless of the 5-HT4 agonist used in the Schild analysis [12]. Thus, values of 8.13, 7.67, 7.63, and 7.68 have been observed for SC-53606 vs. 5-HT, 5-methoxytryptamine, renzapride, and SC-53116, respectively. 

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