GR 113808 is a Potent and Highly Selective 5-HT4 Receptor Antagonist

Serotonin (5-HT) acts as a neurotransmitter in both the central and peripheral nervous systems. Meanwhile, it acts as a paracrine signaling molecule in the periphery.  In the gastrointestinal (GI) tract 5-HT contributes to motility, secretion, vasodilation, and sensation, and it also has both neuroprotective and pro-inflammatory actions in the gut. 5-HT4 is positively coupled to adenylyl cyclase in various isolated tissue preparations. The colonic epithelium highly expresses 5-HT4. Epithelial 5-HT4 receptors mediate a variety of responses, including 5-HT releasing, chloride secretion and goblet cell degranulation, as well as enhanced propulsive motility and reduced visceral hypersensitivity. In addition, the 5-HT4 receptor mediates an increase in heart rate. In this study, GR 113808 is a potent and highly selective 5-HT4 receptor antagonist (pKb= 8.8). GR 113808 shows 300-fold selectivity over 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT3 receptors.

On the guinea-pig ascending colon, GR113808 (1 nM-0.1 μM) behaves as an antagonist of 5-HT-induced contraction. It produces rightward displacements of the concentration-effect curve to 5-HT and a concentration-related depression of the maximum effect. In the guinea-pig colon preparation, it examines the onset and offset of the antagonism by GR113808 of 5-HT-induced contraction. Incubation of the tissues for either 15 min, 30 min or 60 min produces similar rightward displacements of the concentration-effect curves to 5-HT, with no increase in the degree of depression of the maxima with increasing time of incubation. On the other hand, in the anesthetized piglet, GRI13808 is a potent antagonist of 5-methoxytryptamine-induced tachycardia. The compound is ineffective against isoprenaline-induced tachycardia.

In summary, GRI13808 will be a valuable antagonist for studying 5-HT4 receptor mechanisms in vitro and in vivo. It has the potential to be a radioligand for determining 5-HT4 receptor distribution.


le JD, et al.Br J Pharmacol. 1994 Jan;111(1):332-8.