Binding of STW 5 (Iberogast®) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors

Clinical studies with the fixed herbal combination product STW 5 (Iberogast®) have indicated an efficacy comparable to metoclopramide (5-HT3 antagonist) and cisapride (5-HT4 agonist) in functional gastro-intestinal diseases like functional dyspepsia (FD) and irritable bowel syndrome (IBS). Since serotonin (5-HT3 and 5-HT4) and muscarinic M3 receptors are known to play a central role in the etiology of FD and IBS, the extracts contained in STW 5 and several of their phytochemical components were studied in vitro for binding affinities to these receptors of the intestine. STW 5 inhibited the binding of 3H-GR113808 and 3H-4-DAMP to 5-HT4 and M3 receptors, respectively, about 10 times more potently than the binding of 3H-GR65630 to 5-HT3 receptors. IC50 values for STW 5 did correspond to extract dilutions of 1:1000 (M3 binding) and 1:2000 (5-HT4 binding). In addition, STW 5 also potently inhibited the binding to opioid receptors with an IC50 value of 1:2000. Of the nine herbal extracts contained in STW 5, the fresh plant extract of bitter candy tuft (Iberis amara) selectively inhibited binding to M3 receptors, while ethanolic extracts of celandine herb and chamomile flower were selective to 5-HT4, and liquorice root to 5-HT3 receptors. Binding affinities to human recombinant 5-HT3, 5-HT4 and M3 receptors were qualitatively similar to those of the corresponding intestinal receptors. The benzylisoquinoline alkaloid berberine had significant inhibitory action on 5-HT4 and M3 binding, showing IC50 values of 40 ng/ml (100 nM) and 200 ng/ml (500 nM), respectively, but is present in the extract of celandine herb only in traces, so that also for the celandine extract a cooperative effect of several phytochemical constituents can be assumed. These in vitro data indicate that 5-HT4 (to a lesser degree 5-HT3), muscarinic M3, and opioid receptors represent target sites for the treatment of FD and IBS with STW 5 (Iberogast®).