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

ABSTRACT: 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 ?-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.

SUBMITTER: Jeong EJ

PROVIDER: S-EPMC5773938 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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The novel, potent and highly selective 5-HT<sub>4</sub> receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility.

Jeong Eun Jeong EJ Chung Soo Yong SY Hong Han Na HN Oh Se-Woong SW Sim Jae Young JY

British journal of pharmacology 20180106 3

<h4>Background and purpose</h4>5-HT<sub>4</sub> 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.<h4>Experimental approach</h4>The binding affinity and selectivity of YH12852 for human 5-HT<sub>4(a)</sub> receptor in CHO-K1 cells were evaluated using radioligand binding assays, and agonistic activity was assessed using a β-lactamase reporter ...[more]

PMID: 29139561

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Project description:ImportanceEpidemiological data on lower gastrointestinal bleeding (GIB) in the general population are sparse.ObjectiveTo describe the incidence, recurrence, mortality, and case fatality rates of major upper GIB and lower GIB in the general population of Finland between 1987 and 2016.Design, setting, and participantsThis prospective cohort study used data from the 1987 to the 2012 cycles of the National FINRISK Study, a health examination survey that was conducted every 5 years in Finland. Survey participants were adults aged 25 to 74 years who were recruited from a population register by random sampling; those with a history of hospitalization for GIB were excluded. Participants were followed up from survey enrollment to onset of GIB that led to hospitalization, death from any cause, or study end (December 31, 2016). Follow-up was performed through linkage with national electronic health registers. Data were analyzed from February 1, 2019, to January 31, 2020.Main outcomes and measuresIncidence, recurrence, mortality, and case fatality rates for all, upper, lower, and unspecified GIB. Outcome measures were stratified by sex and age group.ResultsAmong the 39 054 participants included in the study, 494 (1.3%) experienced upper GIB (321 men [65.0%]; mean [SD] age, 52.8 [12.1] years) and 645 (1.7%) had lower GIB (371 men [57.5%]; mean [SD] age, 54.0 [11.7] years). The age-standardized incidence rate was 0.94 per 1000 person-years (95% CI, 0.85-1.04) for upper GIB and 1.26 per 1000 person-years (95% CI, 1.15-1.38) for lower GIB; the incidence was higher in men than in women. Between 1987 and 2016 the incidence rate of upper GIB remained mostly stable, ranging from 0.40 to 0.66 per 1000 person-years, whereas constant increases occurred in the incidence of lower GIB until the rate stabilized. The proportion of recurrent GIB events showed an increasing trend from 1987 to 2016. The upper GIB-specific mortality was higher (0.07 per 1000 person-years; 95% CI, 0.04-0.09) than the lower GIB-specific mortality (0.01 per 1000 person-years; 95% CI, 0.001-0.03). Case fatality was high for those with upper GIB (7.0%; 95% CI, 4.7-10.1) compared with those with lower GIB (0.4%; 95% CI, 0.1-1.3). Case fatality remained stable over the years but was higher in men (between 5% and 10%) than women (<2%) with GIB.Conclusions and relevanceThis study found that the overall incidence rate of upper GIB was lower than the incidence of lower GIB, but the recurrence, mortality, and 28-day case fatality were higher in participants with upper GIB. These data can serve as a reference when putting into context the rates of drug-associated GIB and can inform efforts to improve GIB care and outcome and to prevent rebleeding or death for patients with major GIB.

Dataset Information

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

Publications

The novel, potent and highly selective 5-HT<sub>4</sub> receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility.

Similar Datasets

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