Selective and functional 5‐hydroxytryptamine₄ receptor antagonism by SB 207266

Abstract

1 The pharmacology of a novel 5-HT4 receptor antagonist, SB 207266 has been evaluated in vitro in the guinea-pig distal colon longitudinal muscle myenteric plexus (LMMP) and in vivo in the dog Heidenhain pouch. 2 SB 207266 is a highly potent antagonist of 5-HT-evoked, cholinergically-mediated contractions in the guinea-pig distal colon. Low concentrations (0.1-10 nM) produced a parallel shift to the right of the concentration-effect curve (apparent pA2 10.6+0.1) with no significant effect on the maximum response. With higher concentrations of SB 207266 (30 nM and above) the maximum response to 5-HT was reduced. 3 The antagonism seen with SB 207266 cannot be attributed to a non-selective effect since high concentrations (1 tM) had no effect on cholinergically-mediated contractions evoked by the nicotinic receptor agonist DMPP in the same preparation. 4 SB 207266 is not an irreversible antagonist since the effects of the compound were reversible upon washing of the tissue. 5 In the dog Heidenhain pouch, oral (0.1-100 ,ug kg-') and intravenous (0.1-100 ,g kg-') administration of SB 207266 produced a dose-dependent antagonism of the contractions evoked by a bolus intravenous injection of 5-HT. An ID50 for SB 207266 of 1.3 Mg kg-' was obtained following i.v. administration and 9.6 Mg kg-' following oral administration. 6 The antagonistic effects of SB 207266 (0.1-100 yg kg-') in the dog Heidenhain pouch were long lasting since, following oral administration, the response to 5-HT was reduced for at least 135 min. 7 SB 207266 is a highly potent, highly selective and orally active 5-HT4 receptor antagonist. This compound is the first orally active amide to be identified in this class of antagonists and as such is an important new tool in the evaluation of 5-HT4 receptor function both in vitro and in vivo.

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

“…However, these data are difficult to interpret given the absence of an effect of 5‐HT 4 receptor antagonists on the peristaltic reflex caused by intraluminal distension of intact preparations of otherwise‐untreated small intestine; 3 –5 or on the faecal pellet output by conscious mice 8 . Similarly, 5‐HT 4 receptor antagonism did not affect baseline potential differences across different intestinal regions of anaesthetized rats, 21 rat small intestinal motility, 22 sheep gastrointestinal myoelectric activity, 23 canine colonic motility 24 or Heidenhain gastric pouch motility in conscious dogs 25 …”

“…The present study examines the ability of the new, orally active 5‐HT 4 receptor antagonist SB‐207266 25 to prevent some of the gastrointestinal consequences of 5‐HT 4 receptor activation. In addition, we examined the ability of this compound to antagonize the actions of 5‐HT in human intestinal preparations.…”

A new host cell internalisation pathway for SadA‐expressing staphylococci triggered by excreted neurochemicals

“…To investigate which receptors are involved, we tested different specific antagonists of the various 5HT receptors: WAY100635 (5HT1A antagonist [Forster et al, 1995]), SB207266 (5HT4 antagonist [Fedouloff et al, 2001;Wardle et al, 1996]), and ondansetron (5HT3 antagonist [Butler, Hill, Ireland, Jordan, & Tyers, 1988]). To investigate which receptors are involved, we tested different specific antagonists of the various 5HT receptors: WAY100635 (5HT1A antagonist [Forster et al, 1995]), SB207266 (5HT4 antagonist [Fedouloff et al, 2001;Wardle et al, 1996]), and ondansetron (5HT3 antagonist [Butler, Hill, Ireland, Jordan, & Tyers, 1988]).…”

Effects of a serotonin 5-HT4 receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans

“…SB-207266 is a highly potent, orally active, long acting 5-HT 4 antagonist with an approximately 1000-fold greater binding affinity for 5-HT 4 than for other 5-HT and non-5-HT receptors 14. SB-207266 inhibited motor activity induced by serotonin in human ileal circular muscle and prevented 5-HT evoked inhibition of spontaneous activity in human colonic circular muscle strips 3.…”