title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Ito
authors.forename: R
authors.initials: R
authors.lastname: Kawamura
authors.forename: Y
authors.initials: Y
authors.lastname: Isobe
authors.forename: K
authors.initials: K
authors.lastname: Tsuchida
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
authors.forename: S
authors.initials: S
authors.lastname: Higuchi
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D064729:Neurokinin-1 Receptor Antagonists; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002867:Chromones; C097458:GK 128; D007093:Imidazoles; D018727:Muscarinic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013373:Substance P; D001285:Atropine; C042867:spantide