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

Abstract

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 5HT₃ 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.