benzofurans and renzapride

This review introduces new therapeutic options in the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. Therefore, prucalopride and lubiprostone are discussed including their mechanisms and side effects. In addition, other substances that are currently under evaluation such as renzapride and linaclotide are described, since recent results showed a significant effect in patients with constipation. Thus, after the withdrawal of tegaserod due to cardiac side effects, new potent drugs are now available for the treatment of constipation.

Topics: Alprostadil; Benzamides; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Cathartics; Chloride Channel Agonists; Constipation; Humans; Irritable Bowel Syndrome; Lubiprostone; Peptides; Randomized Controlled Trials as Topic; Receptors, Guanylate Cyclase-Coupled; Receptors, Serotonin, 5-HT4

This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT(4) receptor splice variants [h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT4 benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide tegaserod. The rank order of affinities ranging across the splice variants was: tegaserod (pKi: 7.38-7.91) > or = Y-36912 (pKi: 7.03-7.85) = BIMU 1 (pKi: 6.92-7.78) > or = DAU 6236 (pKi: 6.79-7.99) > or = 5-HT (pKi: 5.82-7.29) > or = 5-MeOT (pKi: 5.64-6.83) > or = renzapride (pKi: 4.85-5.56). We obtained affinity values for the 5-HT4(b), (d) and (g) variants for RS67333 (pKi: 7:48-8.29), prucalopride (pKi: 6.86-7.37) and zacopride (pKi: 5.88-7.0). These results indicate that the ligands interact with the same conserved site in each splice variant. Some splice variants have a higher affinity for certain agonists and the direction of selectivity followed a common trend of lowest affinity at the (d) variant. However, this trend was not evident in functional experiments. Our findings suggest that it may be possible to design splice variant selective ligands, which may be of relevance for experimental drugs but may be difficult to develop clinically.

Topics: Aniline Compounds; Animals; Benzamides; Benzimidazoles; Benzofurans; Binding Sites; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Chlorocebus aethiops; COS Cells; Cyclic AMP; Dose-Response Relationship, Drug; Humans; Indoles; Kinetics; Ligands; Piperidines; Protein Isoforms; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists

The serotonin 5-HT(4) receptor has recently gained a lot of attention for its functional roles in central processes such as memory and cognition. In this study, we show that activation of the human 5-HT(4) (h5-HT(4)) receptor stimulates the secretion of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPalpha). 5-HT enhanced the level of secreted sAPPalpha in a time- and dose-dependent manner in Chinese hamster ovary cells stably expressing the h5-HT(4(e)) receptor isoform. The increase was inhibited by the selective 5-HT(4) receptor antagonist, GR113808. The 5-HT(4) selective agonists, prucalopride and renzapride, also increased secreted sAPPalpha in IMR32 human neuroblastoma cells. The stimulatory effect of 5-HT was mimicked by forskolin, a direct activator of adenylyl cyclase, and 8-bromo-cAMP, a membrane-permeant cAMP analogue. On the contrary, inhibition of protein kinase A (PKA) by H89 potentiated the 5-HT-induced increase in both secreted and cellular sAPPalpha. This phenomenon involves a novel PKA-independent stimulatory process that overcomes a PKA-dependent inhibitory one. Finally, activation of the h5-HT(4(e)) receptor did not modify extracellular amyloid beta-protein in Chinese hamster ovary cells transfected with the human APP695. Given the neuroprotective and enhancing memory effects of sAPPalpha, our results may open a new avenue for the treatment of Alzheimer's disease.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adenylyl Cyclases; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Benzamides; Benzofurans; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Colforsin; Cricetinae; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Humans; Indoles; Ligands; Memory; Polymerase Chain Reaction; Protein Binding; Protein Isoforms; Radioimmunoassay; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Sulfonamides; Time Factors; Transfection; Tumor Cells, Cultured

Agonists of the serotonin 5-hydroxytryptamine 4 (5-HT4) receptor are widely used to activate motility in the gastrointestinal tract. Among these, cisapride was recently withdrawn from the U.S. market because of its proarrhythmic effects. Cisapride is a potent blocker of human ether-à-gogo (HERG) K(+) channels and prolongs the cardiac action potential in a reverse use dependence manner. We compared the effects of four different 5-HT4 receptor agonists (cisapride, prucalopride, renzapride and mosapride) on cloned HERG channels with the objective to evaluate and compare their proarrhythmic potential. K(+) currents from HERG-transfected COS-7 cells were recorded under physiological conditions using the whole cell configuration of the patch-clamp technique. Short (500 ms) depolarizing prepulses were used and following deactivating HERG currents were measured. Cisapride inhibited the HERG channels in a concentration-dependent manner with an IC(50) of 2.4 10(-7) M. The IC(50) value for prucalopride to block HERG (5.7 10(-6) M) was 20-fold higher than that of cisapride. Renzapride was slightly more potent than prucalopride (IC(50) = 1.8 10(-6) M). Mosapride produced no significant effects on the recombinant HERG current. The voltage dependence of HERG block was also investigated. The block mediated by cisapride or renzapride was voltage-dependent whereas that produced by prucalopride was not. We conclude that the rank order of potency of 5-HT4 agonists to block HERG is cisapride > renzapride > prucalopride > mosapride. We also conclude that 5-HT4 agonists devoid of side effects on the HERG current such as mosapride can be found as a safe alternative to cisapride.

Topics: Animals; Arrhythmias, Cardiac; Benzamides; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Cation Transport Proteins; Cisapride; DNA-Binding Proteins; Electrophysiology; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Gastrointestinal Agents; Glycosaminoglycans; Humans; Morpholines; Potassium Channels; Potassium Channels, Voltage-Gated; Recombinant Proteins; Serotonin Antagonists; Trans-Activators; Transcriptional Regulator ERG