5‐HT₄ receptor agonists: similar but not the same

Abstract

5-Hydroxytryptamine 4 (5-HT 4 ) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT 4 receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT 4 receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K + channel and tegaserod: 5-HT 1 and 5-HT 2 receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT 4 receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT 4 receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT 4 receptor-related differences between agonists. Based on drug-and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT 4 receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT 4 receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders.

Bloating and functional gastro-intestinal disorders: Where are we and where are we going?

“…Experimental data in healthy controls showed that glucagon, a potent muscle relaxant, reduced abdominal symptoms but gas retention and objective abdominal distension were unaffected [77] . Domperidone has been shown to be ineffective in IBS symptoms [118] whereas the administration of neostigmine, a prokinetic drug, produced gas clearance and improvement of both abdominal symptoms and objective distension [119] . Likewise the 5-HT4 receptor agonist tegaserod has demonstrated potent prokinetic effects on small intestinal and colonic transit in IBS patients with constipation, also reducing the symptoms of bloating [120] .…”

“…For these reasons, its use in clinical practice is very limited. Prucalopride is a highly selective 5-HT4 receptor agonist with strong enterokinetic activity [124,125] and requires lower dose for this therapeutic effect [119] making this drug potentially suitable for bloating patients [126] . Itopride, a dopamine receptors antagonist and acetylcholinesterase inhibitor, has shown conflicting results in patients with functional dyspepsia [127,128] .…”

Clinical and economic profile of prucalopride in the treatment of chronic constipation in women

“…In particolare è stata esplorata la possibilità di favorire il transito intestinale mediante l'azione di procinetici che agiscono come agonisti del recettore serotoninergico 5-HT4. Nel 2009 è stata autorizzata a livello europeo l'immissione in commercio di prucalopride, primo agonista selettivo del recettore 5-HT4 appartenente a una nuova classe di benzofurani, indicato, dietro presentazione di ricetta medica [2], per il trattamento della stipsi cronica idiopatica delle donne dopo il fallimento di altri comuni lassativi [38].…”

Characteristics of 5-Hydroxytryptamine Receptors Involved in Contraction of Feline Ileal Longitudinal Smooth Muscle

“…Approximately 80% of the human body's total 5-HT is located in the enterochromaffin cells in the gut, where it is reported to be involved in intestinal movements via several 5-HT receptor subtypes [3,6]. Based on biochemical and pharmacological criteria, 5-HT receptors are classified into seven main receptor subtypes, five of which are present on enteric neurons, enterochromaffin cells and GI smooth muscles, namely 5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7 [7,8]. With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all 5-HT receptors are G protein-coupled receptors that activate an intracellular second messenger cascades to produce either excitatory or inhibitory responses [8].…”