Effect of the 5-HT receptor agonist tegaserod on the expression of GRK2 and GRK6 in the rat gastrointestinal tract.

Objective: Tegaserod is a 5-hydroxytryptamine type 4 (5-HT) receptor agonist, formerly used in treating constipation predominant irritable bowel syndrome, which desensitizes 5-HT receptors in rat oesophagus and colon in vitro. Desensitization of 5-HT receptors is regulated by G-protein coupled receptor kinases. This study was designed to assess the effect of 5-HT receptor activation on the expression of GRK2 and GRK6 in the rat oesophagus and distal colon by acute administration of tegaserod.

Distribution of 5-HT3, 5-HT4, and 5-HT7 Receptors Along the Human Colon.

Background/aims: Several disorders of the gastrointestinal tract are associated with abnormal serotonin (5-HT) signaling or metabolism where the 5-HT3 and 5-HT4 receptors are clinically relevant. The aim was to examine the distribution of 5-HT3, 5-HT4, and 5-HT7 receptors in the normal human colon and how this is associated with receptor interacting chaperone 3, G protein coupled receptor kin-ases, and protein LIN-7 homologs to extend previous observations limited to the sigmoid colon or the upper intestine.

Methods: Samples from ascending, transverse, descending, and sigmoid human colon were dissected into 3 separate layers (mucosa, lon-gitudinal, and circular muscles) and ileum samples were dissected into mucosa and muscle layers (n = 20).

Assessment of the pharmacological properties of 5-methoxyindole derivatives at 5-HT4 receptors.

Objectives: The aim was to examine the biological activity of 5-methoxytryptamine derivatives at the 5-hydroxytryptamine (5-HT)(4) receptor to explore the effect of substitution on the aliphatic amine of the 5-methoxyamine scaffold.

Methods: Three compounds were tested for affinity at the 5-HT(4) receptor by radioligand binding and functional activity using guinea-pig ileum and human colon circular muscle preparations and also in the mouse whole gut transit test.

Key Findings: The three compounds all had agonist properties at the 5-HT(4) receptor but their efficacy differed in the different functional tests.

Synthesis, testing and structure-activity studies on a library of 5-HT₄ ligands.

Several indole derivatives and analogues comprising a range of related structural classes were designed, synthesized and tested as ligands for the 5-HT₄ receptor. Within each series, binding experiments showed compounds with good affinity demonstrating high percentage displacement values at 1 µM. The most potent of these (20) had a pKi of 8.

Tissue dependent differences in G-protein coupled receptor kinases associated with 5-HT4 receptor desensitization in the rat gastro-intestinal tract.

Desensitization of 5-HT(4) receptors is regulated by G-protein coupled receptor kinases (GRKs). However, the specific GRK(s) that regulates the desensitization of 5-HT(4) receptors in the in vivo setting is unknown. We investigated the in situ expression of 5-HT(4) receptors and the GRKs in the rat gastrointestinal tract using immunohistochemistry and their interaction using coimmunoprecipitation.