Motohiro Takeda (1), Katsura Tsukamoto (1), Yuka Mizutani (1), Tsunemasa
Suzuki (1) and Kohtaro Taniyama (2)
(1) Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Shiosaki,
363, Hokusei-cho, Inabe-gun, Mie 511-0406, Japan
(2) Department of Pharmacology, Nagasaki University School of Medicine,
Sakamoto 1-12-4, Nagasaki 852-8523, Japan
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 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.
Keywords: 5-HT4 receptor, Benzofuran derivative, SK-951, Rat
esophagus, Guinea pig ileum