The in vitro pharmacology and non-clinical cardiovascular safety studies of a novel 5-HT4 receptor agonist, DSP-6952.
The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine4 (5-HT4) receptor agonists. DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT4(b) receptor, and produced contraction in the isolated guinea pig colon with EC50 of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT4 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-HT4 receptor antagonist, and another 5-HT4 receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT4 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-HT4 receptor agonistic activity as well as a favorable cardiovascular safety profile.
['Tsubouchi|Tadashi|T|', 'Kunimatsu|Takeshi|T|', 'Tsujimoto|Shinji|S|', 'Kiyoshi|Akihiko|A|', 'Katsura|Yasunori|Y|', 'Oku|Seiko|S|', 'Chihara|Kazuhiro|K|', 'Mine|Yukiko|Y|', 'Yamada|Toru|T|', 'Shimizu|Isao|I|', 'Bando|Kiyoko|K|']
D000818:Animals D053961:Azabicyclo Compounds D001549:Benzamides D002319:Cardiovascular System D020117:Cisapride D003106:Colon D003331:Coronary Vessels D004285:Dogs D004353:Drug Evaluation, Preclinical D051638:Ether-A-Go-Go Potassium Channels D006168:Guinea Pigs D006801:Humans D007211:Indoles D008252:Macaca fascicularis D008297:Male D009025:Morpholines D009119:Muscle Contraction D032383:Myocytes, Cardiac D018408:Patch-Clamp Techniques D010880:Piperidines D011817:Rabbits D044422:Receptors, Serotonin, 5-HT4 D058828:Serotonin 5-HT4 Receptor Agonists D018170:Sumatriptan
Cardiovascular safety 5-HT(4) receptor agonist Cardiac ischemia Gastrointestinal prokinetic agent QT prolongation