The in vitro pharmacology and non-clinical cardiovascular safety studies of a novel 5-HT 4 receptor agonist, DSP-6952
| Autor: | Akihiko Kiyoshi, Isao Shimizu, Yasunori Katsura, Tadashi Tsubouchi, Kiyoko Bando, Seiko Oku, Shinji Tsujimoto, Toru Yamada, Kazuhiro Chihara, Yukiko Mine, Takeshi Kunimatsu |
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| Rok vydání: | 2018 |
| Předmět: |
Pharmacology
Chronotropic Agonist Tegaserod biology Intrinsic activity business.industry medicine.drug_class hERG 5-HT4 receptor Receptor antagonist 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine stomatognathic system biology.protein Medicine 030211 gastroenterology & hepatology business Receptor medicine.drug |
| Zdroj: | European Journal of Pharmacology. 826:96-105 |
| ISSN: | 0014-2999 |
| Popis: | The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine 4 (5-HT 4 ) receptor agonists. DSP-6952 had a strong affinity of K i = 51.9 nM for 5-HT 4(b) receptor, and produced contraction in the isolated guinea pig colon with EC 50 of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT 4 receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP-6952 showed minimal effects up to 100 μM in human ether-a-go-go-related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP-6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP-6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP-6952 were completely antagonized by a 5-HT 4 receptor antagonist, and another 5-HT 4 receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT 4 receptor agonists, and have not been regarded as a critical issue in clinical use. DSP-6952 did not induce contraction in the rabbit coronary artery up to 100 μM, which differed from tegaserod or sumatriptan. These results show that DSP-6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP-6952 is a promising GI prokinetic compound with partial 5-HT 4 receptor agonistic activity as well as a favorable cardiovascular safety profile. |
| Databáze: | OpenAIRE |
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