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Concentration-response curves of RQ-00201894, human motilin, and erythromycin at human motilin receptors expressed in CHO cells, obtained using a b-lactamase reporter gene assay. Data represent percentage relative to the maximal control activity at 50 mM erythromycin and show arithmetic mean ± SEM of three independent variables.
Source publication
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, tra...
Contexts in source publication
Context 1
... motilin and erythromycin were equi-effective as motilin receptor agonists, the E max values for RQ-00201894 and motilin being similar to the activity evoked by the maximum concentration of erythromycin (50 mM) (Fig. 1). In this assay, the EC 50 values for RQ-00201894, motilin and erythromycin were, respectively, 0.20 (geometric mean with 95% confidence limits: 0.19e0.22), 0.11 (0.07e0.19) and 69 (51e94) nM; the E max values were 101 (99e103), 97 (95e100)% and 98 (95e101)%; and the Hill slopes were 1.5 (1.3e1.7); 1.9 (1.5e2.3) and 1.9 (1.6e2.3) all ...
Context 2
... broadly-similar long-lasting ac- tivity has previously been reported for erythromycin and azi- thromycin, drugs used to treat gastroparesis or increase gastric emptying, and also camicinal, under development for treatment of these disorders (4, 12; see Introduction for more detail). By contrast, a relatively short-lasting activity of motilin is consistent with its physiological role in inducing the migrating phase III contractions of the MMC (1, 4, 12, 16, 17). The explanation for these different profiles of activity for motilin and the synthetic motilin receptor agonists is unclear but 'functional' or 'biased' agonism has been hypothesised, with the molecules acting at one or more binding Table 1 Summary of effects of RQ-00201894 on baseline muscle tension and on neuronally- mediated contractions during electrical field stimulation in human isolated colon. ...
Citations
... 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. ...
... 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). Although extensive efforts have been made to develop MTLR-targeting drug candidates, all these candidates are discontinued in clinical trials because of undesirable safety and effectiveness. ...
Motilin is an endogenous peptide hormone almost exclusively expressed in the human gastrointestinal (GI) tract. It activates the motilin receptor (MTLR), a class A G protein-coupled receptor (GPCR), and stimulates GI motility. To our knowledge, MTLR is the first GPCR reported to be activated by macrolide antibiotics, such as erythromycin. It has attracted extensive attention as a potential drug target for GI disorders. We report two structures of Gq-coupled human MTLR bound to motilin and erythromycin. Our structures reveal the recognition mechanism of both ligands and explain the specificity of motilin and ghrelin, a related gut peptide hormone, for their respective receptors. These structures also provide the basis for understanding the different recognition modes of erythromycin by MTLR and ribosome. These findings provide a framework for understanding the physiological regulation of MTLR and guiding drug design targeting MTLR for the treatment of GI motility disorders.
... 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 . ...
After the discovery of motilin in 1972, motilin and the motilin receptor were studied intensely for their role in the control of gastrointestinal motility and as targets for treating hypomotility disorders. The genetic revolution — with the use of knockout models — sparked novel insights into the role of multiple peptides but contributed to a decline in interest in motilin, as this peptide and its receptor exist only as pseudogenes in rodents. The past 5 years have seen a major surge in interest in motilin, as a series of studies have shown its relevance in the control of hunger and regulation of food intake in humans in both health and disease. Luminal stimuli, such as bitter tastants, have been identified as modulators of motilin release, with effects on hunger and food intake. The current state of knowledge and potential implications for therapy are summarized in this Review.
... At present, only the motilin receptor agonist camicinal appears in clinical development, with others at preclinical stages. Of the latter, RQ00201894 (RaQualia; structure not disclosed), a nonmacrolide small molecule with selective ability to activate the motilin receptor, has recently been shown to cause long-lasting facilitation of cholinergically mediated contractions in human gastric antrum [51]. ...
Introduction: Gastroparesis is defined by nausea, vomiting, pain, early satiety and bloating, and characterized by delayed gastric emptying without obvious structural abnormalities. Metoclopramide is widely used, increasing gastric emptying and inhibiting nausea and vomiting. Other drugs are available in certain countries and some are used ‘off-label’ because they increase gastric emptying or inhibit emesis. However, correlation between gastroparesis symptoms and rates of gastric emptying is poor. For anti-emetic drugs, dose-ranging and Phase III trials in gastroparesis are lacking.
Areas covered: Gastric motility may still be disordered, leading to nausea, even though gastric emptying is unchanged. One hypothesis is that interstitial cells of Cajal (ICC) are damaged by diabetes leading to gastric dysrhythmia and nausea. Novel approaches to treatment of nausea also include the use of ghrelin receptor agonists, highlighting a link between appetite and nausea.
Expert opinion: There is an urgent need to diversify away from historical drug targets. In particular, there is a need to control nausea by regulating ICC functions and/or by facilitating appetite via ghrelin receptor agonists. It is also important to note that different upper gastrointestinal disorders (gastroparesis, chronic unexplained nausea and vomiting, functional dyspepsia) are difficult to distinguish apart, suggesting wider therapeutic opportunity.
... Fujimoto Y et al. | 13 Hence, we can propose the possibility that NCX1 overexpression enhances to extrude Ca 2+ in the smooth muscles in the gastric fundus. Since abnormal productions of NO and PACAP are caused in functional gastrointestinal disorders, the new compounds affecting on NCX could be valuable (22,23,24). Indeed, the functions of NCX in gastrointestinal disorders are an important theme of future study. ...
In gastric smooth muscles, the released Ca²⁺ activates the contractile proteins and Ca²⁺ taken up from the cytosol cause relaxation. The Na⁺/Ca²⁺ exchanger (NCX) is an antiporter membrane protein that controls Ca²⁺ influx and efflux across the membrane. However, the possible relation of NCX in gastric fundus motility is largely unknown. Here, we investigated electric field stimulation (EFS)-induced relaxations in the circular muscles of the gastric fundus in smooth muscle-specific NCX1 transgenic mice (Tg). EFS caused a bi-phasic response, transient and sustained relaxation. The sustained relaxation prolonged for an extended period after the end of the stimulus. EFS-induced transient relaxation and sustained relaxation were greater in Tg than in wild-type mice (WT). Disruption of nitric oxide component by N-nitro-L-arginine, EFS-induced transient and sustained relaxations caused still marked in Tg compared to WT. Inhibition of PACAP by antagonist, EFS-induced sustained relaxation in Tg was not seen, similar to WT. Nevertheless, transient relaxation remained more pronounced in Tg than in WT. Next, we examined responses to NO and PACAP in smooth muscles. The magnitudes of NOR-1, which generates NO, and PACAP-induced relaxations were greater in Tg than in WT. In this study, we demonstrate that NCX1 regulates gastric fundus motility.
Motilin, a peptide hormone consisting of 22 amino acid residues, was identified in the duodenum of pigs in the 1970s. It is known to induce gastrointestinal contractions during the interdigestive state in mammals. Although the motilin gene has been identified in various animal species, it has not been studied in amphibians. Here, we identified the motilin gene in the Japanese fire bellied newt (Cynops pyrrhogaster), and conducted an analysis of tissue distribution, morphological observations, and physiological experiments. The deduced mature newt motilin comprises 22 amino acid residues, like in mammals and birds. The C-terminus of the newt motilin showed high homology with motilin from other species compared to the N-terminus region, which is considered the bioactive site. Motilin mRNA expression in newts was abundant in the upper small intestine, with notably high motilin mRNA expression found in the pancreas. Motilin-producing cells were found in the mucosal layer of the upper small intestine and existed as two cell types: open-and closed-type cells. Motilin-producing cells in the pancreas were also found to produce insulin but not glucagon. Newt motilin stimulated gastric contractions but not in other parts of the intestines in vitro, and motilin-induced gastric contraction was significantly inhibited by treatment with atropine, a muscarinic acetylcholine receptor antagonist. These results indicate that motilin is also present in amphibians, and that its gastrointestinal contractile effects are conserved in mammals, birds, and amphibians. Additionally, we demonstrated for the first time the existence of pancreatic motilin, suggesting that newt motilin has an additional unknown physiological role.
Purpose of review:
In this review, we evaluate recent findings related to the association between gastrointestinal hormones and regulation of gastric emptying.
Recent findings:
Motilin and ghrelin, which act during fasting, promote gastric motility, whereas most of the hormones secreted after a meal inhibit gastric motility. Serotonin has different progastric or antigastric motility effects depending on the receptor subtype. Serotonin receptor agonists have been used clinically to treat dyspepsia symptoms but other hormone receptor agonists or antagonists are still under development. Glucagon-like peptide 1 agonists, which have gastric motility and appetite-suppressing effects are used as a treatment for obesity and diabetes.
Summary:
Gastrointestinal hormones play an important role in the regulation of gastric motility. Various drugs have been developed to treat delayed gastric emptying by targeting gastrointestinal hormones or their receptors but few have been commercialized.
Objective
To test the effect of Banxia Xiexin Decoction (半夏泻心汤, BXD) on the contraction and relaxation of gastric smooth muscle (SM) in diabetic gastroparesis (DGP) model rats, and to explore the mechanism of BXD in the prevention and treatment of DGP through experiments of signal pathway both in vivo and in vitro.Methods
Sixty Sprague-Dawley rats were divided into 6 groups according to a random number table: control group, model group, high-, medium- and low-dose BXD groups (9.2, 4.6 and 1.8 g/(kg·d), respectively), and domperidone group (10 mg/(kg·d)), 10 rats per group. DGP model was established initially by a single intraperitoneal injection of streptozotocin (STZ), and was confirmed by recording gastric emptying, intestinal transport velocity and gastric myoelectric activity of rats after 2 months. Each group was treated with a corresponding drug for 4 weeks. The mRNA and protein expressions of phospholipase C (PLC), inositol triphosphate (IP3), neuronal nitric oxide synthase (nNOS), and cyclic guanosine monophosphate (cGMP) dependent protein kinase G (PKG) were detected by reverse transcription-polymerase chain reaction and Western blot, respectively, while nitric oxide (NO) and cGMP expressions were detected by enzyme-linked immunosorbent assay. Gastric tissues were obtained from rats for primary cell culture preparation. Gastric SM cells were treated with 0.8 µmol/L of STZ or STZ plus 1,000, 500 and 200 µg/mL of BXD or STZ plus 2.5 µmol/mL of domperidone for 24, 48, 72 or 96 h, respectively. The length of gastric SM cells and intracellular Ca2+ concentration ([Ca2+]i) before and after BXD treatment was measured.ResultsCompared with the model group, high- and medium-dose BXD and domperidone significantly increased the expressions of PLC, IP3, NO, nNOS, cGMP and PKG in rat’s gastric tissue (P<0.01). Gastric SM cells treated with BXD showed a time- and dose-dependent increase in cell viability (P<0.01). The treatment with high- and medium-dose BXD and domperidone inhibited the increase in gastric SM cells length and increased [Ca2+]i compared with the model cells (P<0.01).Conclusions
Treatment with high- and medium-dose BXD significantly attenuated STZ-induced experimental DGP in rats. The therapeutic effect of BXD on DGP rats might be associated with the PLC-IP3-Ca2+/NO-cGMP-PKG signal pathway.
Gastroparesis is characterized by delayed gastric emptying with associated symptoms of nausea, postprandial fullness, bloating, upper abdominal pain, early satiety, and, with more severe disease, vomiting in the absence of mechanical obstruction. The most common causes of gastroparesis are idiopathic, diabetic, and postsurgical. Metoclopramide is the only FDA-approved medication for the treatment of gastroparesis. In patients with diabetic gastroparesis, incretin-based medications (e.g., the amylin analog, pramlintide) and GLP-1 analogs (e.g., exenatide, liraglutide) may delay gastric emptying. The general principles of dietary management are based on measures that optimize gastric emptying (e.g., blenderized, low-fat, low-fiber diet) while meeting the patient’s nutritional requirements. There is still considerable unmet need for the medical management of gastroparesis. Novel pharmacotherapy with prucalopride and relamorelin is promising, and endoscopic or laparoscopic interventions (considered elsewhere in this book) may change the landscape of therapeutic interventions for treatment of gastroparesis.
The rest of this book will deal with various biomechanical applications of the theory of soft shells used to study the motility of the human stomach. To understand biological phenomena that underlie complex processes like peristalsis, gastroparesis, myenteric neuropathy, gastric arrhythmia, etc we begin with analysis of the basic myoelectrical phenomena.
