RQ-00201894: A motilin receptor agonist causing long-lasting facilitation of human gastric cholinergically-mediated contractions

Abstract

The aim was to characterise RQ-00201894, a novel non-macrolide motilin agonist, using human recombinant receptors and then investigate its ability to facilitate cholinergic activity in human stomach. A reporter gene assay assessed motilin receptor function. Selectivity of action was determined using a panel of different receptors, ion channels, transporters and enzymes. Cholinergically-mediated muscle contractions were evoked by electrical field stimulation (EFS) of human gastric antrum. The results showed that RQ-00201894, motilin and erythromycin acted as full motilin receptor agonists (EC50: 0.20, 0.11, 69 nM, respectively). In this function, RQ-00201894 had >90-fold selectivity of action over its ability to activate the human ghrelin receptor (EC50 19 nM) and greater selectivity over all other receptors/mechanisms tested. In human stomach RQ-00201894 0.1-30 μM concentration-dependently increased EFS-evoked contractions (up to 1209%; pEC50 6.0). At 0.1-10 μM this activity was usually prolonged. At higher concentrations (3-30 μM) RQ-00201894 also caused a short-lasting muscle contraction, temporally disconnected from the increase in EFS-evoked contractions. RQ-00201894 10 μM did not consistently affect submaximal contractions evoked by carbachol. In conclusion, RQ-00201894 potently and selectively activates the motilin receptor and causes long-lasting facilitation of cholinergic activity in human stomach, an activity thought to correlate with an ability to increase gastric emptying.

Motilin: from gastric motility stimulation to hunger signalling

“…It also increased LES pressure but disrupted oesophageal peristalsis 130 . RQ-00201894, another small molecule agonist, binds to the motilin receptor and has been shown to increase antral contractions in human smooth muscle strips through a cholinergic pathway 219 . The oligopeptide SK-896 binds with similar affinity to the motilin receptor as motilin and contracted smooth muscle in in vitro preparations of the rabbit gastrointestinal tract with the same pharmacological profile as motilin 220 .…”

Structural basis for motilin and erythromycin recognition by motilin receptor

“…The desensitization effect of mitemcinal is much more improved (54). Nonmacrolide small molecular agonists, such as camicinal (GSK-962040), RQ-00201894, and DS-3801b, were designed to improve pharmacokinetics properties and minimize self-desensitization (24)(25)(26). Camicinal is an orally effective MTLR agonist with high receptor selectivity, which shows long-lasting gastric cholinergic activity (51).…”

“…Compared with other gastroparesis prokinetic medications, such as dopamine D2 receptor antagonists and 5-hydroxytryptamine receptor 4 agonists, MTLR agonists are more efficacious in improving gastric motility and limited adverse effects (18,19). A series of motilin analogs (20,21), macrolide derivatives (22,23), and nonmacrolide small molecular ligands have been developed (24)(25)(26). The development of MTLR-targeted drugs will benefit from the mechanistic elaboration of the ligand recognition by MTLR.…”

Gastrointestinal hormones and regulation of gastric emptying

“…Camicinal induces gastric phase III contractions during the fasting state, dose-dependently enhances the gastric emptying rate, and was also found to improve patients' symptoms in a phase 2 study [23][24][25]. Other small molecule motilin receptor agonists accelerated gastric motility in phase 1 trials but none of these have progressed to phase 2 [26,27].…”