The anti-emetic activity of GK-128 in Suncus murinus.
In Suncus murinus, various emetic responses and the anti-emetic activity of a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128 (2-[(2-methylimidazol-1-yl) methyl benzo[f]thiochromen-1-one monohydrochloride hemihydrate), were investigated. Cancer chemotherapeutic agents, cisplatin and cyclophosphamide, dose-dependently induced emesis of long-lasting duration. The 5-HT3 receptor agonist, 2-methyl-5-HT, and copper sulfate also induced emesis of short duration. However, another 5-HT3 receptor agonist, m-chlorophenylbiguanide, was not consistently emetic. GK-128 inhibited the emetic responses induced by chemotherapeutic agents and 2-methyl-5-HT with similar potency. The anti-emetic action of GK-128 was more potent than that of ondansetron, Y-25130, granisetron and metoclopramide. The order of potency of these drugs, except granisetron, was consistent with that of their 5-HT3 receptor binding affinity in rat cortex. GK-128 failed to inhibit copper sulfate-induced emesis. These data suggest that GK-128 has a potent inhibitory effect on emesis via the 5-HT3 receptor, and that the 5-HT3 receptor involved in emesis in Suncus murinus may be different from the classically defined 5-HT3 receptor in other animals such as rats, dogs and ferrets.
Ito
C
C
Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Isobe
Y
Y
Kijima
H
H
Kiuchi
Y
Y
Ohtsuki
H
H
Kawamura
R
R
Tsuchida
K
K
Higuchi
S
S
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity; D003300:Copper / Q000633:toxicity; D019327:Copper Sulfate; D003520:Cyclophosphamide / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012788:Shrews; D013045:Species Specificity; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
D000932:Antiemetics; D002867:Chromones; C097458:GK 128; D007093:Imidazoles; D012702:Serotonin Antagonists; D012701:Serotonin; C045918:2-methyl-5-HT; D003300:Copper; D003520:Cyclophosphamide; D019327:Copper Sulfate; D002945:Cisplatin