5-HT4 antagonism in irritable bowel syndrome (IBS): Effect of SB-207266-A on rectal sensitivity and small bowel transit

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

“…These data imply that in clinical studies, SB‐207266 may be an effective 5‐HT 4 receptor antagonist (e.g. 2 ).…”

“…In addition, although 5‐HT 4 receptor antagonism did not affect colorectal distension‐evoked nociceptive behaviour in untreated rats, 9 such antagonists may prevent the ability of 5‐HT to increase tetrodotoxin‐insensitive Na + currents in type 2 dorsal root ganglia cells 38 and exert anti‐nociceptive activity when the nociceptive reflex is sensitized by stressful or inflammatory intestinal stimuli 14 . As such, although the involvement of 5‐HT in irritable bowel syndrome has not been equivocally proved, 1 the availability of agents such as SB‐207266 now allows the hypothesis to be tested 2 …”

“…The 5‐HT 4 receptor within the gastrointestinal tract may be associated with processes which contribute to disturbed defaecation, watery diarrhoea 1 and perhaps, to the symptoms of irritable bowel syndrome 1 . 2 Thus, activation of this receptor by 5‐HT may sensitize the peristaltic reflex in intact preparations of small 3 –6 and large 7 intestine, increase the excretion of faecal pellets in conscious mice, 8 , 9 evoke chloride 10 , 11 and mucus 12 secretion from the mucosa, induce watery diarrhoea 13 and, in one study with rats and mice, reduce the increased defaecation and sensitivity to visceral pain caused by stress or by large bowel inflammation 14 . These actions of 5‐HT are partly mimicked by the partial 5‐HT 4 receptor agonists cisapride or SDZ HTF 919 (increased intestinal transit, the production of loose stools, occasional abdominal discomfort 15 –17 ), but compared with the full agonist, 5‐HT, the actions of these drugs are limited 18 and, hence, of therapeutic value in patients with reduced gastrointestinal motility.…”

“…Thus, our interest is to explore the possibility of using drugs such as SB‐207266 to understand human bowel pathophysiology 1 . 2 The results obtained using the human tissues have previously been abstracted 26…”

Hypersensitivity and Hyperreactivity in the Irritable Bowel Syndrome: An Opportunity for Drug Discovery

“…Preliminary observations in diarrhoea-predominant IBS patients indicates of 5-HT can be increased postprandially in diarrhoeapredominant IBS patients [85]. The released 5-HT could, that selective 5-HT 4 receptor antagonism by SB-207266 does inhibit the accelerated oro-caecal transit time [105] in theory, activate both 5-HT 3 and 5-HT 4 receptors, functionally the most dominant of the 5-HT receptors within without causing constipation, and this is consistent with all of the above data. the gut.…”