NEW SEROTONIN RECEPTOR AGONISTS
Gastrointestinal (GI) disorders can be caused by disturbances of the transit in the GI tract and can lead to serious health issues. Gut movements in the GI tract are based on the peristaltic reflex which is controlled by the enteric nervous system (ENS) located within the gut wall. In this regard the neurotransmitter serotonin which is released from the epithelium lining the lumen of the gut is responsible for the regulation of gut movements.
The inventors synthezised new hydroxyindalpine derivates (5-Benzyloxyindalpine, 5 BOIP) that act as serotonin receptor 5HT1P agonists and stimulate by this nerve cells of the ENS. 5 BOIP is highly speci- fic, extremely stable against hydrolysis and oxidation and is much more convenient in production than other known agonists. In the proximal stomach, 5BOIP evokes muscle relaxation, thereby improving the gastric accommodation reflex.
Figure: 5-BOIP activates nerve cells of the human enteric nerve systems. 5-BOIP induces action potentials (left curve) which is blocked in the presence of the 5-HT1P antagonist 5-HTTP-DP (middle curve). Action potentials can be induced again after wash out of 5-HTTP-DP and fresh addition of 5-BOIP.
5 BOIP is useful as therapeutic agent for the treatment or prevention of GI diseases such as constipati- on and functional dyspepsia and, in particular, for relieving GI symptoms.
Proof of principle in vitro.