Effects of KW-5617 (Zaldaride Maleate), a Potent and Selective Calmodulin Inhibitor, on Secretory Diarrhea and on Gastrointestinal Propulsion in Rats

抄録

KW-5617 (zaldaride maleate), 1, 3-dihydro-1-[1-[(4-methyl-4H, 6H-pyrrolo[1, 2-α][4, 1]-benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one maleate, is a selective calmodulin inhibitor. We studied the effects of KW-5617 on secretory diarrhea and gastrointestinal propulsion in rats, as compared with those of loperamide, a conventional anti-diarrheal drug. Diarrhea was induced in rats either by 16, 16-dimethyl prostaglandin E₂ (500 μg/kg, i.p.) or by castor oil (1 ml/100 g body weight, p.o.). In the 16, 16-dimethyl prostaglandin E₂ model, KW-5617 at the doses of 3 mg/kg (p.o.) and higher ameliorated the diarrhea. Similarly, loperamide improved the diarrhea, the activity of loperamide being equivalent to that of KW-5617. In the castor oil model, KW-5617 significantly delayed the onset of diarrhea at the doses of 3 mg/kg (p.o.) and higher, while loperamide delayed the onset of diarrhea at the doses of 0.3 mg/kg (p.o.) and higher. KW-5617 only at the high doses of 30 and 100 mg/kg (p.o.) reduced gastric emptying, small intestinal propulsion, proximal colonic propulsion and distal colonic propulsion. In contrast, loperamide at its anti-diarrheal doses inhibited gastrointestinal propulsion. Our results show that KW-5617, unlike loperamide, at its anti-diarrheal doses does not exert anti-propulsive effects in rats. KW-5617 may be a useful drug for the treatment of diarrhea in terms of less side effects such as constipation.