Effect of a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128, on 5-HT3 receptors mediating contractions and relaxations in guinea-pig distal colon

Article

Author: Makoto Muramatsu ; Yoshihiko Isobe ; Reiko Kawamura ; Chika Ito ; Shohei Higuchi ; Katsuharu Tsuchida

1. We investigated 5-hydroxytryptamine3 (5-HT3) receptor-mediating contractions and relaxations in the guinea-pig isolated distal colon using various 5-HT3 receptor agonists and antagonists, including GK-128 (2-[(2-methylimidazol-1-yl) methyl] benzo[f] thiochromen-1-one monohydrochloride hemihydrate). 2. Selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, produced spantide-insensitive contraction and atropine-insensitive contraction and the relaxation. These agonists showed a small, but significant, difference of potency between contraction and relaxation. 3. GK-128 competitively blocked both 2-methyl-5-HT- and m-chlorophenylbiguanide-induced responses with similar potency. The affinities of GK-128 for spantide-insensitive contraction and atropine-insensitive contraction were ten-fold higher than for relaxation. 4. Other selective 5-HT3 receptor antagonists, azasetron and tropisetron, also exhibited higher affinity in contraction than in relaxation, but the extent of their affinity differences was smaller than that observed in GK-128. In contrast, granisetron, ramosetron and ondansetron exhibited no significant differences in their affinity values among the three responses. 5. These results suggest that the 5-HT3 receptors which mediate contraction and relaxation in the guinea-pig distal colon may not be the same, and that GK-128 is a 5-HT3 receptor antagonist with a stronger potency for contraction.

01 Jan 1997·The Journal of pharmacology and experimental therapeutics

Effect of GK-128 [2-[(2-methylimidazol-1-yl)methyl]-benzo[f]thiochromen-1-one monohydrochloride hemihydrate], a selective 5-hydroxytryptamine3 receptor antagonist, on colonic function in rats.

Article

Author: Kiuchi, Y ; Kawamura, R ; Isobe, Y ; Tsuchida, K ; Ito, C ; Higuchi, S

We investigated the effects of various selective 5-hydroxytryptamine (5-HT)3 receptor antagonists, including GK-128 [2-[(2-methylimidazol-1-yl)methyl]benzo[f]thiochromen-1-one monohydrochloride hemihydrate], on colonic function. In conscious rats, 5-HT and a 5-HT3 receptor agonist, 2-methyl-5-HT, dose-dependently increased fecal pellet output, but another 5-HT3 receptor agonist, m-chlorophenylbiguanide, did not affect output. The selective 5-HT3 receptor antagonists GK-128, granisetron, ramosetron, azasetron and ondansetron depressed the increase in fecal pellet output caused by 2-methyl-5-HT and by wrap-restraint stress. However, the rank order of potency of antagonists in the two defecation models was not consistent with that for the von Bezold-Jarisch reflex. Although granisetron and ramosetron dose-dependently reduced the spontaneous excretion of fecal pellets, GK-128 did not affect it. These results suggest that GK-128 may be used for the treatment of stress-induced gastrointestinal dysfunction. Furthermore, the present results suggest that the 5-HT3 receptor involved in colonic motility may be different from the classically defined 5-HT3 receptor and/or that the regulation of colonic motility mediated by 5-HT3 receptors during stress may be different from normal physiological conditions.

01 Oct 1996·Journal of pharmaceutical sciences

Effect of pulverization on dehydration behavior of crystals of GK-128, a serotonin3 receptor antagonist.

Article

Author: Ito, S ; Nishimura, M ; Matsumoto, K ; Itai, S ; Kobayashi, Y ; Yamamoto, K

The effect of pulverization on the dehydration behavior of 2-[(2-methylimidazol-1-yl)methyl]benzo[i]thiochromen-1-one monohydrochloride hemihydrate (GK-128), a newly developed serotonin3 receptor antagonist, was studied using powder X-ray diffraction analysis, thermogravimetry (TG), and differential scanning calorimetry (DSC). The crystalline forms of GK-128 obtained by pulverizing with a jet mill and an agale mortar were each confirmed to be the same as that of intact GK-128, since the powder X-ray diffraction patterns of the two prepared samples were identical with that of intact GK-128. However, after pulverization by jet mill, the dehydration temperature of GK-128 was markedly lowered and the DSC endothermic peak due to dehydration disappeared. The activation energy for dehydration, calculated by the Ozawa method using TG data, decreased with decreasing particle size and/or crystallinity of GK-128 crystals, e.g., the activation energies for dehydration of intact and jet-milled GK-128 were 128.1 and 75.9 kj/mol, respectively. The results of comparison of powder X-ray diffraction patterns of pulverized GK-128 and intact GK-128 and of determination of the crystal structure of GK-128 suggested that water molecules could be removed easily along the c-axis of GK-128 crystals.

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Indication	Highest Phase	Country/Location	Organization	Date
Vomiting	Discovery	JP	Taisho Pharmaceutical Co., Ltd.	-

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