5-HT4 receptors

Saturated N-heterocycles with serotonin 5-HT3 and 5-HT4 receptor binding affinities 98YGK851. 

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. 

Two 5-HT receptor sub-types, 5-HT3 and 5-HT4, are involved in gut motility, visceral sensitivity, and gut secretion. The 5-HT3 receptors slow colonic transit and increase fluid absorption, whereas 5-HT4 receptor stimulation results in accelerated colonic transit. 

Tegaserod maleate (Zelnorm) stimulates 5-HT4 receptors in the GI tract, thereby increasing intestinal secretion, peristalsis, and small bowel transit. It also reduces sensitivity related to abdominal distention. It has been shown to be more effective than placebo in improving global IBS symptoms and altered bowel habits in constipation-predominant IBS.21 Diarrhea is a possible adverse effect. 

Assess 5-HT4 receptor agonists (tegaserod) for relief of crampy abdominal pain and bloating. 

In the periphery, 5-HT4 receptor mRNA is found in vascular smooth muscle. Newly developed drugs that activate 5-HT4 receptors are of interest for their potential in treating cardiac arrhythmia. The 5-HT4 receptor is also located on neurons of the alimentary tract, for example the myenteric plexus of the ileum, and on smooth muscle cells and secretory cells of the gastrointestinal tract, where they evoke secretions and the peristaltic reflex. 5-HT4 receptor agonists (e.g. cisapride, prucalopride, tegaserod) are used therapeutically in the treatment of constipation-predominant irritable bowel syndrome and in functional motility disorders of the upper gastrointestinal tract. 

Barnes, J. M. and Barnes, N. M. Neurochemical consequen-sces following pharmacological manipulation of central 5-HT4 receptors. In R. M. Eglen (ed.), 5-HT4 Receptors Brain Periphery. Berlin Springer, 1998, pp 103-126. 

Test Systems Addressing 5-HT4 Receptor Agonist Activity 197... 

The 5-HT4 receptor is a member of the seven transmembrane-spanning G protein-coupled family of receptors (GPCR) and constitutes an important subtype of the class of serotonin (5-HT) receptors. Initially, the 5-HT4 receptor was characterized in the neuronal cell culture [3] of mouse colliculi and was shown to be positively coupled to adenylyl cyclase. The effect of serotonin was mimicked by the 5-HT4 receptor agonists, BIMU 1 and BIMU 8, and was blocked by the 5-HT4... 

In the central nervous system (CNS) of guinea-pigs and rats, 5-HT4 receptors are expressed in two anatomical and functional structures the extrapyramidal motor system and the mesolimbic system [6,7]. In human brain, the presence of 5-HT4 receptors has been shown in basal ganglia and in the caudate putamen nuclei, where the density is the highest [8]. 

HT4 receptors are also present in the pig and human hearts, primarily located in the atrium [9]. Experiments showed that stimulation of these receptors can result in tachycardia and can trigger positive inotropic effects. Moreover, it has been demonstrated that the 5-HT4 receptor is present in the human detrusor muscle and facilitates a cholinergic mechanism which may lead to increased bladder contractions [10]. Finally, acute (but not repeated) stimulation of 5-HT4 receptors present on the human adrenal cortex has been reported to trigger the release of corticosterone and aldosterone [11]. 

In almost all tissues where 5-HT4 receptors are present, 5-HT or any other agonists increase intracellular cAMP synthesis [12], as has been shown for hippocampus, atrium, esophagus, intestinal tissue and adrenal cortex. A number of processes can be triggered by an increase in intracellular cAMP. For instance in the intestine, an increase in intracellular cAMP concentrations following activation of 5-HT4 receptors can trigger a relaxation of the smooth muscle. However, activation of 5-HT4 receptors present on intestinal inter- and motor-neurons leads to a facilitation of acetylcholine release and, thereby, to increased contractions of intestinal smooth muscle [13]. 

TEST SYSTEMS ADDRESSING 5-HT4 RECEPTOR AGONIST ACTIVITY... 

The activities of the indole carbazimidamide derivatives 5 at the 5-HT4 receptor were measured in vitro using the field-stimulated LMMP-GPI preparation (Table 1) followed by in vivo investigations applying the gastric emptying and intestinal transit models in the guinea-pig and rat. 

Additionally, tegaserod at low nanomolar concentrations increases intracellular cAMP concentrations in crypt cells isolated from rat distal colon and stimulates chloride and water secretion by activation of 5-HT4 receptors [34,35], These findings suggest a modulatory effect on intestinal electrolyte and water secretion in vivo. 

Figure 1 Inhibition by tegaserod of neuronal activity (firing rate) of rectal spinal afferents (n = 9) upon distention (50 mmHg) of feline colon and the antagonism by SB 203186, a competitive inhibitor at 5-HT4 receptors. From Schikowski et al. Neurogastroenterol. Mot. (2002), 14 221-227.

The 5-HT4 receptor has been identified in mouse brain (positively coupled to adenylate cylcase) and guinea pig ileum (associated with gastroprokinetic activity) [151]. 

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