The novel, potent and highly selective 5-HT4 receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility.

BACKGROUND AND PURPOSE: 5-HT4 receptor agonists have been shown to be effective at treating various gastrointestinal tract disorders. However, a lack of selectivity against off-targets has been a limiting factor for their clinical use. EXPERIMENTAL APPROACH: The binding affinity and selectivity of YH12852 for human 5-HT4(a) receptor in CHO-K1 cells were evaluated using radioligand binding assays, and agonistic activity was assessed using a ß-lactamase reporter system. Contractile activity and propulsive motility were measured in the guinea pig isolated distal colon. Its prokinetic effect on the gastrointestinal tract was evaluated in guinea pigs, dogs and monkeys. Its tissue distribution was evaluated in rats. KEY RESULTS: YH12852 exhibited high affinity and potency for human recombinant 5-HT4(a) receptor with high selectivity over other 5-HT and non-5-HT receptors, ion channels, enzymes and transporters. YH12852 induced contractions and increased propulsive motility in guinea pig isolated colon. These effects were abolished by the 5-HT4 receptor antagonist GR113808. YH12852 increased defecation more effectively than prucalopride in guinea pigs and dogs and improved gastric emptying more effectively than mosapride in guinea pigs, dogs and monkeys. YH12852 was highly distributed to the gastrointestinal tract as the target organ. CONCLUSION AND IMPLICATIONS: The high in vitro potency and selectivity of YH12852 for 5-HT4 receptor translated into potent in vivo efficacy with good tolerability. YH12852 significantly improved both upper and lower bowel motility in the animal models tested and has the potential to address considerable unmet needs in patients with functional constipation, gastroparesis or both.

Analysis of the effects diclofenac has on Japanese medaka (Oryzias latipes) using real-time PCR.

The expression levels of cytochrome P450 1A, p53 and vitellogenin were investigated in three different tissues of male medaka fish after exposure to diclofenac that is one of the main concerns among pharmaceuticals frequently found in sewage treatment plant (STP) effluents. The results showed that cytochrome P450 1A, p53 and vitellogenin were highly expressed in tissue-specific gene expression patterns after exposure to 8 mg/l and 1 microg/l of diclofenac. These elevated expression levels of three biomarkers suggested that diclofenac has potential to cause cellular toxicity, p53-related genotoxicity and estrogenic effects. It is also noteworthy that diclofenac has the potential to cause these effects even at an environmentally relevant concentration of diclofenac, 1 microg/l.

Gene expression analysis and classification of mode of toxicity of polycyclic aromatic hydrocarbons (PAHs) in Escherichia coli.

Escherichia coli is known to respond to certain toxic chemicals through an increased expression of various stress genes. In this study, therefore, the expression of recA, katG, fabA and grpE genes was used as a representative for DNA, oxidative, membrane and protein damage, respectively, after E. coli was exposed to different polycyclic aromatic hydrocarbons (PAHs), i.e., phenanthrene, naphthalene and benzo[a]pyrene. To accomplish this, the expression levels of these four genes were quantified using a real-time RT-PCR analysis when E. coli cultures were under stressful conditions, such as those caused by an exposure to mitomycin C, hydrogen peroxide and phenol. It was found that the primary toxic effect of each chemical is clearly seen when the expression levels of the different genes are compared. Tests with the PAHs showed naphthalene and benzo[a]pyrene to be genotoxic, while phenanthrene had no clear effect on the expression of any of these genes. Based on these results, the effects due to these toxic chemicals and the extent of each stress can be evaluated with ease using the expression levels of different stress responsive genes.