Seiko Oku

DSP-6952, a novel 5-HT 4 receptor partial agonist, inhibits visceral hypersensitivity and ameliorates gastrointestinal dysfunction in experimental animals

&NA; The pharmacological profile of DSP‐6952, a novel 5‐HT4 receptor partial agonist, was investigated to evaluate the potential use for GI disorders, and to compare its effects in some GI dysfunction models with those of clinically efficacious prokinetic agents. DSP‐6952 enhanced gastric motility and caused colonic giant migrating contractions (GMCs) associated with defecation in conscious dogs, having ED50 value for inducing GMCs of 1.56 mg/kg. DSP‐6952 (3–10 mg/kg, i.g.) significantly enhanced colonic transit rate in guinea pigs; this enhancement was antagonized by SB‐207266, a selective 5‐HT4 receptor antagonist. DSP‐6952 (1–10 mg/kg, p.o.) rapidly increased fecal wet weight without increasing fluid content in mice. Sennoside (30–100 mg/kg, p.o.) also increased fecal wet weight; however, it significantly increased fluid content with diarrhea. DSP‐6952 dose‐dependently improved clonidine‐ and morphine‐induced delay in whole‐gut transit in mice (ED50= 0.429 mg/kg and 0.310 mg/kg, respectively), which represented atonic and spastic constipation models, respectively. In viscerally hypersensitive rats treated with acetic acid, DSP‐6952 (10 mg/kg, i.p., 30 mg/kg, p.o., 30 mg/kg, i.c.) and tegaserod (1 mg/kg, i.p.), but not prucalopride (10 mg/kg, i.p.), significantly inhibited the increase in colorectal distension‐induced visceromotor response; these findings suggest that DSP‐6952 and tegaserod inhibit visceral hypersensitivity in rats. It was concluded that DSP‐6952, a novel and orally available 5‐HT4 receptor agonist, induced colonic GMCs, enhanced colonic transit, increased defecation without inducing diarrhea, improved drug‐induced delay in whole‐gut transit, and inhibited visceral hypersensitivity in experimental animals. Therefore, DSP‐6952 is expected to become a useful drug for treatment of IBS‐C and chronic constipation.

The in vitro pharmacology and non-clinical cardiovascular safety studies of a novel 5-HT 4 receptor agonist, DSP-6952

&NA; 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 &mgr;M 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 &mgr;M, 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.