HT4 partial agonist

If drugs are used, the first choice should be a bulk laxative, e.g. isphagula or sterculia gum. Nonabsorbent carbohydrates with osmotic activity also work well but often cause flatulence. Salinic laxatives like polyethylene glycol and magnesium oxide are very effective but often cause stomach upsets like flatulence and abdominal pain. Tegaserod, a 5-HT4 partial agonist, appears to improve the frequency of bowel movements in those with chronic constipation (see Evans et ah, 2007). 

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. 

Chemical structure of serotonin the 5-HT3 antagonists ondansetron, granisetron, dolasetron, and alosetron and the 5-HT4 partial agonist tegaserod. 

Brodney MA, Johnson DE, Sawant-Basak A, Coffman KJ, Drummond EM, Hudson EL et al (2012) Identification of multiple 5-HT4 partial agonist clinical candidates for the treatment of Alzheimer s disease. J Med Chem 55 9240-9254... 

Possible functions of the 5-HT4 receptor have been recently reviewed [47,48,49]. In the CNS, 5-HT4 activation increases cAMP in the hippocampus [50]. This observation has led to behavioral studies using cognition models. 5-HT4 receptor activation induces relaxation of the esophagus [51,52] and increases cAMP accumulation in this tissue [53]. These data indicate a possible role for the 5-HT4 receptor in GERD. A selective 5-HT4 partial agonist, cisapride, has been used clinically for gastroprokinesis for many years prior to the elucidation of its molecular site of action. Functional 5-HT4 receptors have also been demonstrated in the guinea pig ileum [54] and in the cardiac atrium, in which increases in cAMP accumulation can also be detected [55]. Such functions indicate possible roles of the 5-HT4 receptor in irritable bowel syndrome and in arrhythmia. 

Tegaserod maleate (Zelnorm) is a partial serotonin (5-HT4) receptor agonist that causes an increase in peristaltic activity and intestinal secretion and moderation of visceral sensitivity. It increases the frequency of bowel movements and reduces abdominal discomfort, bloating, and straining. It is indicated for the treatment of patients younger than 65 years of age who experience chronic idiopathic constipation. The most common adverse effects include headache, abdominal pain, diarrhea, and nausea. 

Pharmacoiogy Tegaserod, a 5-HT4 receptor partial agonist, triggers the release of... 

Lamirault L, Simon H. Enhancement of place and object recognition memory in young adult and old rats by RS 67333, a partial agonist of 5-HT4 receptors. Neuropharmacology 2001 41 844-853. 

A subclass of serotonin receptors dubbed 5-HT4 are involved in regulation of intestinal motility. The partial agonist tegaserod (22) has proven useful in treating conditions characterized by decreased motility, such as irritable bowel syndrome. The drug is interestingly prescribed specifically for use in women, since results from clinical trials indicated poor response in men. Alkylation of thiosemicarbazone (18) with methyl iodide proceeds on sulfur to the thioether (19). Treatment of intermediate 19 with pentyl-1-amine leads to addition of the amine to the thioether function followed by... 

Muller-Lissner SA, EumagalU I, BardUan KD, et al. Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. AUment Pharmacol Ther 2001 15 1655-1666. 

By 1988, it was known that the 5-HT-induced tachycardia in pig was neither mimicked nor antagonized by a variety of 5-HTi 2,3-R ligands, and was therefore necessarily mediated by a new subtype of 5-HT-R [89]. A similar observation was made by Kaumann et al. in human atrium, in which a non-5-HTi 2,3-R increased contractile force via an increase in c-AMP and PKA activity [24]. Since this receptor was blocked by mM concentrations of tropisetron, this suggested that 5-HT4-R subtype was involved. Later, it was shown that both right and left hxunan atria express 5-HT4-RS where benzamides are partial agonists [32, 90]. The... 

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. 

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