Identification of SK-951, a Novel Benzofuran Derivative, as an Agonist to 5-HT_4 Receptors

• Published in: Japanese Journal of Pharmacology 1999, Vol.79 (2), p.203-212
• Main Authors: Motohiro Takeda, Katsura Tsukamoto, Yuka Mizutani, Tsunemasa Suzuki, Kohtaro Taniyama
• Format: Article
• Language: Japanese
• ISSN: 0021-5198

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-HT_3 and 5-HT_4 receptors by the receptor binding assay and functional studies. The receptor binding assay showed that SK-951 bound to the 5-HT_3 receptor with a high affinity, to the 5-HT_4 receptor with relatively higher affinity and to the muscarinic M_2 receptor with a low affinity, but not to dopamine D_1 and D_2 and serotonin 5-HT_1 and 5-HT_2 and muscarinic M_1 and M_3 receptors. SK-951 caused relaxations of tunica muscularis mucosae preparations from rat esophagus which were precontracted with carbachol, and the effects were antagonized by GR13808, a selective 5-HT_4 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-HT_1 , 5-HT_2 and 5-HT_3 receptors were blocked, and it enhanced the electrically-stimulated release of [^^3 H]acetylcholine (ACh). These effects of SK-951 were antagonized by GR113808. SK-951 inhibited the 5-HT_3 receptor-mediated contractions. These results indicate that SK-951 possesses properties of an agonist for the 5-HT_4 receptor and an antagonist for the 5HT_3 receptor. Thus, SK-951 is a new and potent 5-HT_4 -receptor agonist and causes contractions of guinea pig ileum mediated by enhancement of ACh release via the 5-HT_4 receptor.