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

Abstract

The pharmacological profile of DSP-6952, a novel 5-HT 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 ED 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-HT 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 (ED= 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-HT 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.

Randomised clinical trial: minesapride vs placebo for irritable bowel syndrome with predominant constipation

“…The affinity for the 5‐HT 4 receptors is almost comparable to that in prucalopride 16 . Minesapride has potent enterokinetic effects and shows minimal effects on human Ether‐a‐go‐go related gene potassium channels in pre‐clinical studies 16,17 . In clinical studies, a phase 1 (first in human) study showed minesapride exposure in plasma increased in a dose‐proportional manner with acceptable safety profile up to 120 mg/d 18 .…”

Comparison of the Gut Microbiota Disturbance in Rat Models of Irritable Bowel Syndrome Induced by Maternal Separation and Multiple Early-life Adversity

“…Several opioid, cannabinoid, and 5-HT receptors play critical roles in visceral hypersensitivity and abnormal gut motility associated with IBS and also contribute to the maladaptive effects of chronic morphine analgesia including hyperalgesia, tolerance, and dependence [29][30][31]. Therefore, we speculate that the visceral hyperalgesia induced by MAM modeling may be mediated by interactions between microorganisms and their host receptors.…”

Editorial: minesapride for irritable bowel syndrome with constipation—authors' reply

“…In studies with non-clinical endpoints, minesapride enhanced gastrointestinal motility and colonic transit and inhibited visceral hypersensitivity. 6 These results suggested possible efficacy in IBS-C. As for cardiovascular risks, unlike tegaserod, minesapride has negligible binding affinities for the 5-hydroxytryptamine (5-HT) 1B/1D or other receptors presumably involved in vasoconstriction. Moreover, minesapride showed no contractile response on isolated coronary arteries.…”