We examined whether delayed gastric emptying could be produced by diabetes in dogs. Diabetes was produced by a single injection of streptozotocin (30 mg/kg i.v.), and diabetic hyperglycemia was observed from 2 to 15 months after injection. The plasma acetaminophen concentration, which is an indirect indicator of the gastric emptying rate, was delayed in 2 of 5 diabetic dogs from 15 months after the induction of diabetes. The effects of SK-951, a benzofuran derivative, on delayed gastric emptying were also examined in diabetic gastroparetic dogs in comparison with those of cisapride. SK-951 (1 mg/kg i.v.) significantly enhanced delayed gastric emptying in diabetic dogs, but cisapride (1 mg/kg i.v.) had no effect. In addition, SK-951 increased the plasma glucose levels in a manner correlated with its effect on gastric emptying. The present study suggested that SK-951 may be useful in the treatment of diabetic gastroparesis.

01 Jan 2000·Japanese Journal of Pharmacology

Facilitation of Acetylcholine Release by SK-951, a Benzofuran Derivative, via the 5-Hydroxytryptamine4 Receptor in Guinea Pig Stomach

Article

Author: Suzuki, Tsunemasa ; Sakurai-Yamashita, Yasuko ; Takeda, Motohiro ; Tsukamoto, Katsura ; Taniyama, Kohtaro

Facilitation of acetylcholine (ACh) release by SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0] octan-5-yl)ethyl]-5-chloro-2,3-dihydro-2-methylbenzo[b]furan-7-carboxami de hemifumarate), a benzofuran derivative, via the 5-hydroxytryptamine (5-HT)4 receptor in guinea pig stomach was examined by in vitro receptor autoradiography and functional studies. [125I]SB207710 binding was detected in the myenteric plexus of the gastric corpus. High densities of binding sites were observed in the myenteric plexus and a moderate density in the muscle layer. SK-951 inhibited the binding of [125I]SB207710, a specific 5-HT4-receptor ligand, as in the case of SB204070, a specific 5-HT4-receptor antagonist, thus indicating the presence of 5-HT4 receptors in guinea pig stomach. SK-951 as well as 5-HT enhanced the electrically stimulated twitch contractions of gastric corpus strips, which were sensitive to tetrodotoxin and atropine, and enhanced electrically stimulated release of ACh from corporal strips, which was tetrodotoxin-sensitive and Ca2+-dependent. The enhancements of twitch contractions and ACh release by SK-951 were antagonized by GR113808, a selective 5-HT4-receptor antagonist. Thus, SK-951 binds to 5-HT4 receptors of the guinea pig gastric corpus and may accelerate gastric motility due to facilitation of ACh release.

01 Jan 1999·Japanese Journal of Pharmacology

Identification of SK-951, a Novel Benzofuran Derivative, as an Agonist to 5-HT4 Receptors

Article

Author: Suzuki, Tsunemasa ; Mizutani, Yuka ; Takeda, Motohiro ; Tsukamoto, Katsura ; Taniyama, Kohtaro

The pharmacological profile of SK-951 ((-)4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl) ethyl]-5-chloro-2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide hemifumarate) was identified in relation to serotonin 5-HT3 and 5-HT4 receptors by the receptor binding assay and functional studies. The receptor binding assay showed that SK-951 bound to the 5-HT3 receptor with a high affinity, to the 5-HT4 receptor with relatively higher affinity and to the muscarinic M2 receptor with a low affinity, but not to dopamine D1 and D2 and serotonin 5-HT1 and 5-HT2 and muscarinic M1 and M3 receptors. SK-951 caused relaxations of tunica muscularis mucosae preparations from rat esophagus which were precontracted with carbachol, and the effects were antagonized by GR113808, a selective 5-HT4 antagonist. In the longitudinal muscle with myenteric plexus (LMMP) preparations from guinea pig ileum, SK-951 enhanced the electrically-stimulated contraction of preparations in which the 5-HT1, 5-HT2 and 5-HT3 receptors were blocked, and it enhanced the electrically-stimulated release of [3H]acetylcholine (ACh). These effects of SK-951 were antagonized by GR113808. SK-951 inhibited the 5-HT3 receptor-mediated contractions. These results indicate that SK-951 possesses properties of an agonist for the 5-HT4 receptor and an antagonist for the 5-HT3 receptor. Thus, SK-951 is a new and potent 5-HT4-receptor agonist and causes contractions of guinea pig ileum mediated by enhancement of ACh release via the 5-HT4 receptor.

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Indication	Highest Phase	Country/Location	Organization	Date
Gastrointestinal Diseases	Discovery	JP	Sanwa Kagaku Kenkyusho Co., Ltd.	-

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