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

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The pharmacological profile of SK-951 ((-)4-amino-<I>N</I>-[2-(1-azabicyclo[3.3.0]octan-5-yl) ethyl]-5-chloro-2, 3-dihydro-2-methylbenzo[<I>b</I>]furan-7-carboxamide hemifumarate) was identified in relation to serotonin 5-HT<SUB>3</SUB> and 5-HT<SUB>4</SUB> receptors by the receptor binding assay and functional studies. The receptor binding assay showed that SK-951 bound to the 5-HT<SUB>3</SUB> receptor with a high affinity, to the 5-HT<SUB>4</SUB> receptor with relatively higher affinity and to the muscarinic M<SUB>2</SUB> receptor with a low affinity, but not to dopamine D<SUB>1</SUB> and D<SUB>2</SUB> and serotonin 5-HT<SUB>1</SUB> and 5-HT<SUB>2</SUB> and muscarinic M<SUB>1</SUB> and M<SUB>3</SUB> 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-HT<SUB>4</SUB> 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<SUB>1</SUB>, 5-HT<SUB>2</SUB> and 5-HT<SUB>3</SUB> receptors were blocked, and it enhanced the electrically-stimulated release of [<SUP>3</SUP>H]acetylcholine (ACh). These effects of SK-951 were antagonized by GR113808. SK-951 inhibited the 5-HT<SUB>3</SUB> receptor-mediated contractions. These results indicate that SK-951 possesses properties of an agonist for the 5-HT<SUB>4</SUB> receptor and an antagonist for the 5HT<SUB>3</SUB> receptor. Thus, SK-951 is a new and potent 5-HT<SUB>4</SUB>-receptor agonist and causes contractions of guinea pig ileum mediated by enhancement of ACh release via the 5-HT<SUB>4</SUB> receptor.

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  • The Japanese journal of pharmacology

    The Japanese journal of pharmacology 79(2), 203-212, 1999-02-01

    The Japanese Pharmacological Society

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各種コード

  • NII論文ID(NAID)
    10008682354
  • NII書誌ID(NCID)
    AA00691188
  • 本文言語コード
    ENG
  • 資料種別
    REV
  • ISSN
    00215198
  • NDL 記事登録ID
    4663513
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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