SB-207266 - 5-HT4 RECEPTOR ANTAGONISM IN HUMAN ISOLATED GUT AND PREVENTION OF 5-HT-EVOKED SENSITIZATION OF PERISTALSIS AND INCREASED DEFECATION IN ANIMAL-MODELS

SB-207266 is a new 5-HT4 receptor antagonist which in a pilot study re duced the symptoms of irritable bowel syndrome. To help validate this and further studies, we examined the ability of SB-207266 to antagoniz e at the human 5-HT4 receptor (human isolated intestine) and to affect the mechanisms of peristalsis (guinea-pig isolated ileum) and defaeca tion (conscious, fed mice). In the human intestine, the potency of 5-H T4 receptor antagonism (pK(B) 9.98) was similar to that previously dem onstrated using a guinea-pig model of the receptor, validating the use of SB-207266 in clinical trials. In each of the animal models, SB-207 266 did not affect normal patterns of intestinal motility measured in the absence of exogenous 5-HT. However, SB-207266 10-1000 pM concentra tion-dependently antagonized the ability of 5-HT (0.1 mu M) to sensiti ze 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. SE-207266 was maximally active at 10 mu g kg(-1) s.c. and 1000 mu g k g(-1) p.o. SB-207266 may therefore represent a new class of therapeuti c agent, capable of preventing the actions of an important sensitizer of gut function.