The novel, potent and highly selective 5-HT4receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility

Autor: Soo Yong Chung, Se-Woong Oh, Jae-Young Sim, Han Na Hong, Eun Jeong Jeong
Rok vydání: 2018
Předmět:
Zdroj: British Journal of Pharmacology. 175:485-500
ISSN: 0007-1188
Popis: Background and Purpose 5-HT4 receptor agonists have been shown to be effective to treat various gastrointestinal tract disorders. However, a lack of selectivity against off-targets has been a limiting factor. 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 beta-lactamase reporter system. Contractile activity and propulsive motility were measured in isolated guinea pig distal colon. The prokinetic effect on the gastrointestinal tract was evaluated in guinea pigs, dogs and monkeys. The tissue distribution study was conducted in rats. Key Results YH12852 exhibited high affinity (pKi=10.3) and potency (pEC50=11.4) 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 significantly induced contractions (pEC50=8.4) and propulsive motility (0.1-10 nM) in isolated guinea pig colon. These effects were abolished by the 5-HT4 receptor antagonist GR113808. YH12852 significantly 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 the 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.
Databáze: OpenAIRE
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