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.
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.
Sanger
G J
GJ
SmithKline Beecham Pharmaceuticals, Neuroscience Research Department, Harlow, Essex, UK.
Banner
S E
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Smith
M I
MI
Wardle
K A
KA
D000284:Administration, Oral; D000818:Animals; D003672:Defecation / Q000187:drug effects*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000627:therapeutic use*; D007410:Intestinal Diseases / Q000517:prevention & control; D007422:Intestines / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010528:Peristalsis / Q000187:drug effects*; D010880:Piperidines / Q000627:therapeutic use*; D012702:Serotonin Antagonists / Q000627:therapeutic use*
D007211:Indoles; D010880:Piperidines; C096919:SB 207266; D012702:Serotonin Antagonists