SB-207266: 5-HT4 receptor antagonism in human isolated gut and prevention of 5-HT-evoked sensitization of peristalsis and increased defaecation in animal models

Neurogastroenterol Motil. 1998 Aug;10(4):271-9. doi: 10.1046/j.1365-2982.1998.00106.x.


SB-207266 is a new 5-HT4 receptor antagonist which in a pilot study reduced the symptoms of irritable bowel syndrome. To help validate this and further studies, we examined the ability of SB-207266 to antagonize at the human 5-HT4 receptor (human isolated intestine) and to affect the mechanisms of peristalsis (guinea-pig isolated ileum) and defaecation (conscious, fed mice). In the human intestine, the potency of 5-HT4 receptor antagonism (pKB 9.98) was similar to that previously demonstrated using a guinea-pig model of the receptor, validating the use of SB-207266 in clinical trials. In each of the animal models, SB-207266 did not affect normal patterns of intestinal motility measured in the absence of exogenous 5-HT. However, SB-207266 10-1000 pM concentration-dependently antagonized the ability of 5-HT (0.1 microM) to sensitize the peristaltic reflex and lower the distension threshold at which peristalsis was evoked. In mice, oral or subcutaneous (s.c.) doses of SB-207266 dose-dependently prevented the ability of the 5-HT precursor, 5-hydroxytryptophan (5-HTP, 10 mg kg-1 s.c.) to increase both the rate of defaecation of formed faecal pellets and their fluid content. SB-207266 was maximally active at 10 micrograms kg-1 s.c. and 1000 micrograms kg-1 p.o. SB-207266 may therefore represent a new class of therapeutic agent, capable of preventing the actions of an important sensitizer of gut function.

MeSH terms

  • Administration, Oral
  • Animals
  • Defecation / drug effects*
  • Disease Models, Animal
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Indoles / therapeutic use*
  • Intestinal Diseases / prevention & control
  • Intestines / drug effects*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Peristalsis / drug effects*
  • Piperidines / therapeutic use*
  • Serotonin Antagonists / therapeutic use*


  • Indoles
  • Piperidines
  • SB 207266
  • Serotonin Antagonists