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Theo L. Peeters - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and characterization of site specific biotinylated probes for the Motilin Receptor
    International Journal of Peptide and Protein Research, 2009
    Co-Authors: Mark J Macielag, Theo L. Peeters, Inge Depoortere
    Abstract:

    The solid-phase synthesis of two porcine Motilin derivatives, specifically biotinylated on the side chain of Lys20, was accomplished by preactivation of the protected amino acids N alpha-(9-fluorenylmethoxycarbonyl)-N epsilon-biotinyl-L-lysine and N alpha-(9-fluorenylmethoxycarbonyl)-N epsilon-[N-(biotinyl)-6-aminohexanoyl]-L-lysine with BOP/HOBt/DIEA (1:1:2.5) followed by coupling to the support-bound peptide substrate. The biotin moiety was stable to TFA cleavage and repetitive cycles of acylation, as evidenced by the high level of purity (> 80%) of the crude peptides. This direct synthetic approach complements existing orthogonal protection strategies for the site-specific biotinylation of peptides. The derivatized peptides were purified by RP-HPLC and characterized by mass spectral and amino acid analysis. In binding studies using a rabbit antral smooth muscle homogenate, both [Leu13, Lys20 (N epsilon-biotinyl)]porcine Motilin (3) and [Leu13, Lys20 (N epsilon-[N-(biotinyl)-6-aminohexanoyl])]porcine Motilin (4) possessed nearly equal affinities for the Motilin Receptor (IC50 = 0.89 and 1.2 nM, respectively) as native porcine Motilin (1) (IC50 = 0.76 nM). The biotinylated peptides were also highly potent in tissue bath assays employing rabbit duodenal smooth muscle segments. In contrast, commercially available [N alpha-biotinylPhe1]porcine Motilin (5) had markedly lower affinity in the binding assay (IC50 = 30 nM). The relative bioactivities of these Receptor probes are in accord with previous synthetic studies on Motilin which demonstrated the importance of the amino-terminal segment in the high affinity interaction between the peptide and its Receptor. Analog 3 retained high affinity for the Motilin Receptor in the presence of avidin. Therefore, this peptide is expected to be a valuable tool for the isolation and identification of Motilin Receptors.

  • oral administration of ma 2029 a novel selective and competitive Motilin Receptor antagonist inhibits Motilin induced intestinal contractions and visceral pain in rabbits
    European Journal of Pharmacology, 2008
    Co-Authors: Hirokazu Sudo, Kenichi Ozaki, Hiroyasu Muramatsu, Kenji Yogo, Kenshi Kamei, Shoshin Yoshida, Mitsu Onoma, Osamu Cynshi, Osamu Kuromaru, Theo L. Peeters
    Abstract:

    Abstract The pharmacological properties of MA-2029, a novel Motilin Receptor antagonist, were investigated. In vitro , MA-2029 (1 to 30 nM) competitively inhibited Motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA 2 value of 9.17 ± 0.01 ( n  = 5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 μM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [ 125 I]Motilin to Motilin Receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human Motilin Receptors. The p K i of MA-2029 was 8.58 ± 0.04 in the rabbit colon homogenate ( n  = 4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo , orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by Motilin (3 μg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of Motilin (3 μg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive Motilin Receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.

  • Differences in Motilin Receptor desensitization after stimulation with Motilin or motilides are due to alternative Receptor trafficking
    Biochemical pharmacology, 2007
    Co-Authors: Anna Mitselos, Theo L. Peeters, Pieter Vanden Berghe, Inge Depoortere
    Abstract:

    Abstract Backgrounds & aims The Motilin Receptor (MTLR) is an important therapeutic target for treatment of hypomotility disorders. The negative outcome in clinical trials with the Motilin agonist, ABT-229, indicated that desensitization may limit the therapeutic usefulness of motilides. We therefore compared the mechanisms involved in the intracellular trafficking of the MTLR after stimulation with Motilin, erythromycin-A (EM-A) or ABT-229. Methods Desensitization was studied by measuring changes in Ca 2+ rises and by Receptor binding studies in CHO cells co-expressing the Ca 2+ indicator apoaequorin and the MTLR, C-terminally tagged with EGFP. Receptor phosphorylation was studied by immunoprecipitation. MTLR-EGFP trafficking to organelles and translocation of β-arrestins were visualized by fluorescence microscopy. Results Agonist-induced desensitization of the MTLR was due to Receptor internalization with potencies (p-int 50 ) in the order of: ABT-229 (8.3) > Motilin (7.86) > EM-A (4.77) but with no differences in the internalization kinetics ( t 1/2 : ∼25 min). The percentage cell surface Receptor loss was more profound after exposure to ABT-229 (88 ± 1%) than to Motilin (63 ± 10%) or EM-A (34 ± 2%). For Motilin and EM-A MTLR phosphorylation probably occurs via G protein-coupled Receptor kinases while for ABT-229 phosphorylation was also protein kinase C dependent. All agonists translocated cytosolic β-arrestin-2 with greater affinity to the plasma membrane than β-arrestin-1. After internalization the MTLR co-localized with transferrin but not with cathepsin D. After stimulation with Motilin and EM-A the t 1/2 for MTLR resensitization was 3 h and 1 h, respectively but amounted 26 h for ABT-229. Conclusion Our results suggest that the resensitization kinetics determine the desensitization properties of the Motilin agonists.

  • Motilin and erythromycin a share a common binding site in the third transmembrane segment of the Motilin Receptor
    Biochemical Pharmacology, 2005
    Co-Authors: Inge Depoortere, Patrick Robberecht, Pascale Vertongen, Magali Waelbroeck, Theo L. Peeters
    Abstract:

    Abstract The Motilin Receptor (MTLR) represents a clinically useful pharmacological target, as agonists binding to the MTLR have gastroprokinetic properties. In order to compare the molecular basis for interaction of the MTLR with Motilin and with the non-peptide Motilin agonist, erythromycin-A (EM-A), the negatively charged E 119 located in the third transmembrane (TM 3 ) region was mutated to D (E119D) and Q (E119Q), respectively, and changes in activity of the mutant Receptors were verified. Methods: Each mutant Receptor was stably transfected in CHO-cells containing the Ca 2+ indicator apo-aequorin. Receptor activation in response to Motilin, EM-A and their analogues was assessed by Ca 2+ -luminescense. Results: In the E119Q mutant, the Ca 2+ response to Motilin and EM-A was abolished while in the E119D mutant it was reduced with 62% (Motilin) and 81% (EM-A). The pEC 50 values were shifted from 9.65 ± 0.03 to 7.41 ± 0.09 (Motilin) and from 6.63 ± 0.12 to 4.60 ± 0.07 (EM-A). Acetylation of the N-terminal amine group as in [ N -acetyl-Phe] 1 mot (1–14), decreased the potency 6.3-fold (WT-MTLR) and 148-fold (E119D). Acetylation of EM-A enol ether induced a more pronounced shift in potency: 7943-fold (WT-MTLR) and 1413-fold (E119D). Conclusion: The comparable loss of affinity of the mutant Receptors for Motilin and EM-A indicate that these agonists both interact with the TM 3 domain of the MTLR. The results with acetylated derivatives support an ionic interaction between E 119 of the MTLR with the N + of the desosamine sugar in EM-A, but not with the N + of the free amine group in Motilin.

  • Desensitization of the Human Motilin Receptor by Motilides
    The Journal of pharmacology and experimental therapeutics, 2005
    Co-Authors: Leen Thielemans, Inge Depoortere, Christopher Carreras, Jason Perret, Patrick Robberecht, Yaoquan Liu, Theo Thijs, Emmanuel Burgeon, Theo L. Peeters
    Abstract:

    Tachyphylaxis may have contributed to the failure of the motilide ABT-229 [ N -ethyl, N -methyl 4′′ deoxy erythromycin (EM)-B enolether] in clinical trials. We compared the desensitizing potency of structurally related motilides [EM-A, EM-A enolether (ME4), N -ethyl, N -methyl EM-A (ME36), EM-B enolether (ME67), N -ethyl, N -methyl EM-A enolether (EM523), ABT-229 and 4′′ deoxy EM-A enolether (KOS1326)] in a Chinese hamster ovary (CHO)-K1 cell line expressing the human Motilin Receptor (MTLR) and in rabbit duodenal segments. CHO-MTLR cells were preincubated with motilides prior to stimulation with Motilin. The negative logarithm of the preincubation concentration reducing the maximal Motilin-induced Ca 2+ flux to 50% was calculated (pDC 50 ). Internalization was visualized in CHO-K1 cells containing an enhanced green fluorescent protein (EGFP)-tagged MTLR and quantified in binding experiments. The contractile response of repeated stimulations was measured in duodenal segments. In CHO-MTLR cells, the pDC 50 was ABT-229 (8.78) > Motilin (7.77) > EM-A (4.78), different from their order of potency to induce Ca 2+ release (pEC 50 ): Motilin (9.39) > ABT-229 (8.46) > EM-A (7.11). In cells with the EGFP-tagged MTLR, ABT-229 decreased membrane fluorescence by 25 ± 2% compared with 16 ± 2% for Motilin and 8 ± 2% for EM-A. Binding studies confirmed that EM-A did not induce MTLR internalization (residual binding 96 ± 4% compared with Motilin, 31 ± 3% and ABT-229, 21 ± 1%). Comparison of the pDC 50 and pEC 50 values of the other motilides ME4 (5.90; 8.08), ME67 (6.03; 8.12), ME36 (3.32; 6.62), EM-523 (6.02; 8.22), and KOS1326 (7.32; 8.14) suggested that the strong desensitizing properties of ABT-229 are mostly related to the removal of the 4″-OH of the cladinose sugar. The decline of the contractile response in duodenal segments correlated with the pDC 50 . The ability to desensitize and internalize the MTLR is not only determined by potency. This may be an important criterion for the development of a clinically useful compound.

Inge Depoortere - One of the best experts on this subject based on the ideXlab platform.

  • effect of Motilin Receptor activation on food intake and food timing
    The American Journal of Clinical Nutrition, 2018
    Co-Authors: Eveline Deloose, Inge Depoortere, Jessica R Biesiekierski, Hanne Vanheel, Jan Tack
    Abstract:

    Background Motilin plasma concentrations are positively correlated with hunger ratings during the fasting state. Moreover, the Motilin agonist erythromycin stimulates meal requests. Objectives The first aim of the study was to evaluate the effect of erythromycin on ad libitum food intake. The second aim was to study the involvement of endogenous Motilin and octanoylated ghrelin on voluntary meal initiations. Design Study 1: Fourteen healthy participants were studied twice after an overnight fast. Intravenous administration of placebo (saline) or erythromycin (40 mg) was given in a double-blind randomized order. Participants had the opportunity to eat ad libitum from an excess free-choice buffet (2330 kcal) for the duration of 1 h. The primary outcome was total caloric intake. Study 2: Thirteen healthy participants were studied after an overnight fast. Baseline blood samples were collected before a breakfast (245 kcal). After a rest period of 90 min, blood samples were collected every 15 min for a duration of 5 h. During this period, volunteers could request small meal portions (164 kcal/serving) at time points of their choosing and unlimited in numbers. The primary outcome was the determination of plasma concentrations before postbreakfast spontaneous meal requests. Results Ad libitum food intake did not differ between placebo and erythromycin groups (difference compared with placebo: 79 kcal; 95% CI: -245.9, 403.97 kcal; P = 0.3). Octanoylated ghrelin concentrations before spontaneous meal requests were, on average, 36% (95% CI: 5.8%, 65.7%; P = 0.02) higher than values before breakfast, whereas Motilin concentrations did not increase (6% increase: 95% CI: -5.9%, 17.2% increase; P = 0.3). Conclusions Motilin Receptor stimulation during the fasting state does not affect total caloric intake nor does endogenous Motilin stimulate meal requests after breakfast in the current study population. This trial was registered at www.clinicaltrials.gov as NCT03024879.

  • manometric evaluation of the Motilin Receptor agonist camicinal gsk962040 in humans
    Neurogastroenterology and Motility, 2018
    Co-Authors: Eveline Deloose, Inge Depoortere, George E Dukes, J De Hoon, A Van Hecken, Odile Dewit, L Vasist S Johnson, Matthew E Barton, Jan Tack
    Abstract:

    BACKGROUND The gut hormone Motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule Motilin Receptor agonist, has been shown to increase gastrointestinal motility. METHODS In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial. KEY RESULTS The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH. CONCLUSIONS AND INFERENCES Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848.

  • the Motilin Receptor agonist erythromycin stimulates hunger and food intake through a cholinergic pathway
    The American Journal of Clinical Nutrition, 2016
    Co-Authors: Eveline Deloose, Inge Depoortere, Rita Vos, Pieter Janssen, Omer Van Den Bergh, Lukas Van Oudenhove, Jan Tack
    Abstract:

    BACKGROUND Motilin-induced phase III contractions have been identified as a hunger signal. These phase III contractions occur as part of the migrating motor complex (MMC), a contractility pattern of the gastrointestinal tract during fasting. The mechanism involved in this association between subjective hunger feelings and gastrointestinal motility during the MMC is largely unknown, however, as is its ability to stimulate food intake. OBJECTIVES We sought to 1) investigate the occurrence of hunger peaks and their relation to phase III contractions, 2) evaluate whether this relation was cholinergically driven, and 3) assess the ability of the Motilin Receptor agonist erythromycin to induce food intake. DESIGN An algorithm was developed to detect hunger peaks. The association with phase III contractions was studied in 14 healthy volunteers [50% men; mean ± SEM age: 25 ± 2 y; mean ± SEM body mass index (BMI; in kg/m(2)): 23 ± 1]. The impact of pharmacologically induced phase III contractions on the occurrence of hunger peaks and the involvement of a cholinergic pathway were assessed in 14 healthy volunteers (43% men; age: 29 ± 3 y; BMI: 23 ± 1). Last, the effect of erythromycin administration on food intake was examined in 15 healthy volunteers (40% men; age: 28 ± 3 y; BMI: 22 ± 1). RESULTS The occurrence of hunger peaks and their significant association with phase III contractions was confirmed (P < 0.0001). Pharmacologically induced phase III contractions were also significantly associated with hunger peaks (P < 0.05), and this association involved a cholinergic pathway. Administering erythromycin significantly stimulated food intake compared with placebo (53% ± 13% compared with 10% ± 5%; P < 0.05). CONCLUSIONS Motilin-induced phase III contractions induced hunger feelings through a cholinergic pathway. Moreover, erythromycin stimulated food intake, suggesting a physiologic role of Motilin as an orexigenic signal from the gastrointestinal tract. This trial was registered at www.clinicaltrials.gov as NCT02633579.

  • synthesis and characterization of site specific biotinylated probes for the Motilin Receptor
    International Journal of Peptide and Protein Research, 2009
    Co-Authors: Mark J Macielag, Theo L. Peeters, Inge Depoortere
    Abstract:

    The solid-phase synthesis of two porcine Motilin derivatives, specifically biotinylated on the side chain of Lys20, was accomplished by preactivation of the protected amino acids N alpha-(9-fluorenylmethoxycarbonyl)-N epsilon-biotinyl-L-lysine and N alpha-(9-fluorenylmethoxycarbonyl)-N epsilon-[N-(biotinyl)-6-aminohexanoyl]-L-lysine with BOP/HOBt/DIEA (1:1:2.5) followed by coupling to the support-bound peptide substrate. The biotin moiety was stable to TFA cleavage and repetitive cycles of acylation, as evidenced by the high level of purity (> 80%) of the crude peptides. This direct synthetic approach complements existing orthogonal protection strategies for the site-specific biotinylation of peptides. The derivatized peptides were purified by RP-HPLC and characterized by mass spectral and amino acid analysis. In binding studies using a rabbit antral smooth muscle homogenate, both [Leu13, Lys20 (N epsilon-biotinyl)]porcine Motilin (3) and [Leu13, Lys20 (N epsilon-[N-(biotinyl)-6-aminohexanoyl])]porcine Motilin (4) possessed nearly equal affinities for the Motilin Receptor (IC50 = 0.89 and 1.2 nM, respectively) as native porcine Motilin (1) (IC50 = 0.76 nM). The biotinylated peptides were also highly potent in tissue bath assays employing rabbit duodenal smooth muscle segments. In contrast, commercially available [N alpha-biotinylPhe1]porcine Motilin (5) had markedly lower affinity in the binding assay (IC50 = 30 nM). The relative bioactivities of these Receptor probes are in accord with previous synthetic studies on Motilin which demonstrated the importance of the amino-terminal segment in the high affinity interaction between the peptide and its Receptor. Analog 3 retained high affinity for the Motilin Receptor in the presence of avidin. Therefore, this peptide is expected to be a valuable tool for the isolation and identification of Motilin Receptors.

  • desensitization and internalization of the human Motilin Receptor is independent of the c terminal tail
    Peptides, 2008
    Co-Authors: Anna Mitselos, Theo Peeters, Inge Depoortere
    Abstract:

    Abstract The Motilin Receptor (MTLR) is an important therapeutic target for the treatment of hypomotility disorders but desensitization may limit its clinical utility. The aim of this study was to investigate the role of the C-terminal tail of the MTLR in the desensitization, phosphorylation and internalization process. Three MTLR mutants, C-terminally truncated from amino acid 412 till 384 (MTLRΔ385), 374 (MTLRΔ375) or 368 (MTLRΔ369), were constructed and C-terminally tagged with an EGFP and stably expressed in CHO cells co-expressing the Ca 2+ indicator apoaequorin. Activity and desensitization were studied by measuring changes in Motilin-induced luminescent Ca 2+ rises. Receptor phosphorylation was investigated by immunoprecipitation and MTLR-EGFP internalization was visualized by fluorescence microscopy. Truncation only reduced MTLR affinity and the efficacy to induce Ca 2+ luminescent responses of the MTLRΔ375-EGFP mutant. Furthermore, the region between amino acid 375 and 368 seems to be important for proper cell surface expression of the MTLR since Receptors of the MTLRΔ369-EGFP mutant but not of the other mutants were found intracellularly in vesicles. Truncation of the Receptor till amino acid 384 or 374 did neither affect desensitization nor internalization. In contrast phosphorylation of the MTLRΔ385-EGFP mutant was reduced by 80% but was not affected in the MTLRΔ375-EGFP mutant. In conclusion, MTLR desensitization and internalization is not dependent on the presence of the C-terminal tail. Truncation favors internalization via either phosphorylation-independent pathways or via phosphorylation of alternative sites in the Receptor.

Gareth J Sanger - One of the best experts on this subject based on the ideXlab platform.

  • Motilin Receptor in gtopdb v 2021 2
    IUPHAR BPS Guide to Pharmacology CITE, 2021
    Co-Authors: Anthony P. Davenport, Takio Kitazawa, Gareth J Sanger
    Abstract:

    Motilin Receptors (provisional nomenclature) are activated by Motilin, a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a Motilin-associated peptide. There are significant species differences in the structure of Motilin and its Receptor. In humans and large mammals such as dog, activation of these Receptors by Motilin released from endocrine cells in the duodenal mucosa during fasting, induces propulsive phase III movements. This activity is associated with promoting hunger in humans. Drugs and other non-peptide compounds which activate the Motilin Receptor may generate a more long-lasting ability to increase cholinergic activity within the upper gut, to promote gastrointestinal motility; this activity is suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; e.g. erythromycin, azithromycin), although for many of these molecules the evidence is sparse. Relatively high doses may induce vomiting and in humans, nausea.

  • rq 00201894 a Motilin Receptor agonist causing long lasting facilitation of human gastric cholinergically mediated contractions
    Journal of Pharmacological Sciences, 2016
    Co-Authors: John Broad, Nobuyuki Takahashi, Masaomi Tajimi, Masaki Sudo, Adam Goralczyk, Umesh Parampalli, Kesava R Mannur, Toshinori Yamamoto, Gareth J Sanger
    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.

  • ghrelin and Motilin Receptor agonists time to introduce bias into drug design
    Neurogastroenterology and Motility, 2014
    Co-Authors: Gareth J Sanger
    Abstract:

    Ghrelin and Motilin Receptor agonists increase gastric motility and are attractive drug targets. However, 14 years after the Receptors were described (18-24 years since ligands became available) the inactivity of the ghrelin agonist TZP-102 in patients with gastroparesis joins the list of unsuccessful Motilin agonists. Fundamental questions must be asked. Pustovit et al., have now shown that the ghrelin agonist ulimorelin evokes prolonged increases in rat colorectal propulsion yet responses to other ghrelin agonists fade. Similarly, different Motilin agonists induce short- or long-lasting effects in a cell-dependent manner. Together, these and other data create the hypothesis that the Receptors can be induced to preferentially signal ('biased agonism') via particular pathways to evoke different responses with therapeutic advantages/disadvantages. Biased agonism has been demonstrated for ghrelin. Are Motilin agonists which cause long-lasting facilitation of human stomach cholinergic function (compared with Motilin) biased agonists (e.g., camicinal, under development for patients with gastric hypo-motility)? For ghrelin, additional complications exist because the therapeutic aims/mechanisms of action are uncertain, making it difficult to select the best (biased) agonist. Will ghrelin agonists be useful treatments of nausea and/or as suggested by Pustovit et al., chronic constipation? How does ghrelin increase gastric motility? As gastroparesis symptoms poorly correlate with delayed gastric emptying (yet gastro-prokinetic drugs can provide relief: e.g., low-dose erythromycin), would low doses of ghrelin and Motilin agonists relieve symptoms simply by restoring neuromuscular rhythm? These questions on design and functions need addressing if ghrelin and Motilin agonists are to reach patients as drugs.

  • Motilin: towards a new understanding of the gastrointestinal neuropharmacology and therapeutic use of Motilin Receptor agonists.
    British journal of pharmacology, 2013
    Co-Authors: Gareth J Sanger, Y Wang, A Hobson, John Broad
    Abstract:

    The gastrointestinal hormone Motilin has been known about for >40 years, but after identification of its Receptor and subsequent development of new tools and methods, a reappraisal of its actions is required. Firstly, it is important to note that Motilin and ghrelin Receptors are members of the same family (similar genomic organization, gastrointestinal distribution and abilities to stimulate gastrointestinal motility), yet each fails to recognize the ligand of the other; and whereas ghrelin and ghrelin Receptors are widespread outside the gastrointestinal tract, Motilin and its Receptors are largely restricted to the gastrointestinal tract. Secondly, although some studies suggest Motilin has activity in rodents, most do not, and Receptor pseudogenes exist in rodents. Thirdly, Motilin preferentially operates by facilitating enteric cholinergic activity rather than directly contracting the muscle, despite the relatively high expression of Receptor immunoreactivity in muscle. This activity is ligand-dependent, with short-lasting actions of Motilin contrasting with longer-lasting actions of the non-selective and selective Motilin Receptor agonists erythromycin and GSK962040. Finally, the use of erythromycin (also an antibiotic drug) to treat patients requiring acceleration of gastric emptying has led to concerns over safety and potential exacerbation of antibiotic resistance. Replacement Motilin Receptor agonists derived from erythromycin (motilides) have been unsuccessful. New, non-motilide, small molecule Receptor agonists, designed to minimize self-desensitization, are now entering clinical trials for treating patients undergoing enteral feeding or with diabetic gastroparesis. Thus, for the translational pharmacologist, the study of Motilin illustrates the need to avoid overreliance on artificial systems, on structural information and on animal studies. Linked Articles This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7

  • the antibiotic azithromycin is a Motilin Receptor agonist in human stomach comparison with erythromycin
    British Journal of Pharmacology, 2013
    Co-Authors: John Broad, Gareth J Sanger
    Abstract:

    Background and Purpose The antibiotic azithromycin is a suggested alternative to erythromycin for treating patients with delayed gastric emptying. However, although hypothesized to activate Motilin Receptors, supportive evidence is unavailable. This was investigated using recombinant and naturally expressed Motilin Receptors in human stomach, comparing azithromycin with erythromycin. Experimental Approach [125I]-Motilin binding and calcium flux experiments were conducted using human recombinant Motilin Receptors in CHO cells. Neuromuscular activities were studied using circular muscle of human gastric antrum, after electrical field stimulation (EFS) of intrinsic nerves. Key Results Azithromycin (1–100 μM) and erythromycin (3–30 μM) concentration-dependently displaced [125I]-Motilin binding to the Motilin Receptor (52 ± 7 and 58 ± 18% displacement at 100 and 30 μM respectively). Azithromycin, erythromycin and Motilin concentration-dependently caused short-lived increases in intracellular [Ca2+] in cells expressing the Motilin Receptor. EC50 values were, respectively, 2.9, 0.92 and 0.036 μM (n = 3 each); and maximal activities were similar. In human stomach, EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. Azithromycin and erythromycin lactobionate (30–300 μM each) facilitated these contractions (apparent Emax values of 2007 ± 396 and 1924 ± 1375%, n = 3–4 each concentration, respectively). These actions were slow in onset and faded slowly. The higher concentrations also evoked short-lived muscle contraction. Contractions to a submaximally effective concentration of carbachol were unaffected by either drug. Conclusions and Implications Azithromcyin activates human recombinant Motilin Receptors in therapeutically relevant concentrations, similar to erythromycin. In humans, gastric antrum azithromycin caused long-lasting facilitation of cholinergic activity. These actions explain the gastric prokinetic activity of azithromycin.

Bunzo Matsuura - One of the best experts on this subject based on the ideXlab platform.

  • characterization of the gastric motility response to human Motilin and erythromycin in human Motilin Receptor expressing transgenic mice
    PLOS ONE, 2019
    Co-Authors: Shinichi Kato, Tomoe Kawamura, Aoi Takahashi, Mai Shindo, Ayano Yoshida, Kenjiro Matsumoto, Bunzo Matsuura
    Abstract:

    Motilin is a gastrointestinal peptide hormone that stimulates gastrointestinal motility. Motilin is produced primarily in the duodenum and jejunum. Motilin Receptors (MTLRs) are G protein-coupled Receptors that may represent a clinically useful pharmacological target as they can be activated by erythromycin. The functions of Motilin are highly species-dependent and remain poorly understood. As a functional Motilin system is absent in rodents such as rats and mice, these species are not commonly used for basic studies. In this study, we examine the usefulness of human MTLR-overexpressing transgenic (hMTLR-Tg) mice by identifying the mechanisms of the gastric motor response to human Motilin and erythromycin. The distribution of hMTLR was examined immunohistochemically in male wild-type (WT) and hMTLR-Tg mice. The contractile response of gastric strips was measured isometrically in an organ bath, while gastric emptying was determined using phenol red. hMTLR expression was abundant in the gastric smooth muscle layer. Interestingly, higher levels of hMTLR expression were observed in the myenteric plexus of hMTLR-Tg mice but not WT mice. hMTLR was not co-localized with vesicular acetylcholine transporter, a marker of cholinergic neurons in the myenteric plexus. Treatment with human Motilin and erythromycin caused concentration-dependent contraction of gastric strips obtained from hMTLR-Tg mice but not from WT mice. The contractile response to human Motilin and erythromycin in hMTLR-Tg mice was affected by neither atropine nor tetrodotoxin and was totally absent in Ca2+-free conditions. Furthermore, intraperitoneal injection of erythromycin significantly promoted gastric emptying in hMTLR-Tg mice but not in WT mice. Human Motilin and erythromycin stimulate gastric smooth muscle contraction in hMTLR-Tg mice. This action is mediated by direct contraction of smooth muscle via the influx of extracellular Ca2+. Thus, hMTLR-Tg mice may be useful for the evaluation of MTLR agonists as gastric prokinetic agents.

  • Effects of Motilin Receptor Agonists and Ghrelin in Human Motilin Receptor Transgenic Mice
    MDPI AG, 2019
    Co-Authors: Tomoe Kawamura, Bunzo Matsuura, Teruki Miyake, Masanori Abe, Yoshiou Ikeda, Yoichi Hiasa
    Abstract:

    Gastrointestinal motility is regulated by neural factors and humoral factors. Both Motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human Motilin Receptor transgenic (Tg) mice and performed experiments evaluating the effects of Motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic Receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) Receptor agonist), and improved loperamide (a μ-opioid Receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of Motilin Receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis

  • characterization of the gastric motility response to human Motilin and erythromycin in human Motilin Receptor expressing transgenic mice
    bioRxiv, 2018
    Co-Authors: Shinichi Kato, Tomoe Kawamura, Aoi Takahashi, Mai Shindo, Ayano Yoshida, Kenjiro Matsumoto, Bunzo Matsuura
    Abstract:

    Abstract Motilin is a gastrointestinal peptide hormone that stimulates gastrointestinal motility. Motilin is produced primarily in the duodenum and jejunum. Motilin Receptors (MTLRs) are G protein-coupled Receptors that may represent a clinically useful pharmacological target as they can be activated by erythromycin. The functions of Motilin are highly species-dependent and remain poorly understood. As a functional Motilin system is absent in rodents such as rats and mice, these species are not commonly used for basic studies. In this study, we examine the usefulness of human MTLR-overexpressing transgenic (hMTLR-Tg) mice by identifying the mechanisms of the gastric motor response to human Motilin and erythromycin. The distribution of hMTLR was examined immunohistochemically in male wild-type (WT) and hMTLR-Tg mice. The contractile response of gastric strips was measured isometrically in an organ bath, while gastric emptying was determined using phenol red. hMTLR expression was abundant in the gastric smooth muscle layer but more potently expressed in the myenteric plexus of hMTLR-Tg mice but not WT mice. hMTLR was not co-localized with vesicular acetylcholine transporter, a marker of cholinergic neurons in the myenteric plexus. Treatment with human Motilin and erythromycin caused concentration-dependent contraction of gastric strips obtained from hMTLR-Tg mice but not from WT mice. The contractile response to human Motilin and erythromycin in hMTLR-Tg mice was affected by neither atropine nor tetrodotoxin and was totally absent in Ca2+-free conditions. Furthermore, intraperitoneal injection of erythromycin significantly promoted gastric emptying in hMTLR-Tg mice but not in WT mice. Human Motilin and erythromycin stimulate the gastric motor response in hMTLR-Tg mice. This action is mediated by direct contraction of smooth muscle via the influx of extracellular Ca2+. Thus, hMTLR-Tg mice may be useful for the evaluation of MTLR agonists as gastric prokinetic agents.

  • sa1745 critical residues in the transmembrane helical bundle domains of the human Motilin Receptor for Motilin and erythromycin binding and activity
    Gastroenterology, 2013
    Co-Authors: Bunzo Matsuura, Teruki Miyake, Masanori Abe, Yoshiou Ikeda, Sachiko Utsunomiya, Teru Kumagi, Yasuhiko Toudou, Shin Yamamoto, Hiroaki Nunoi, Yoichi Hiasa
    Abstract:

    Background: Activated pancreatic stellate cells (PSC) play an important role in chronic pancreatitis to exacerbate fibrosis and increase the risk of pancreatic cancer. Systemic dysregulation of glucose metabolism, increased rates of obesity and type II diabetes are rising at an alarming pace in the Western world. Hyperinsulinemia and glucose intolerance associated with these disorders may have a variety of deleterious effects on the pancreas, an organ with a vital role to regulate glucose in the whole body. However, the extent to which these effects involve PSC has not been determined. Methods: we analyzed the expression of insulin/ IGF-1 signaling pathway components and their operation as profibrotic and/or proliferative pathways within a novel immortalized human pancreatic stellate cell line (ihPSC) and assessed the potential contributions of these cells to a procarcinogenic microenvironment. Results: ihPSC express Receptors for both insulin (IR) and insulin-like growth factor 1 (IGF-1R), and respond to insulin/IGF-1 stimulation with increased tyrosine phosphorylation at specific autophosphorylation sites. Whereas routine culture conditions (DMEM/F12 supplemented with 10% FBS) maintained constitutive tyrosine autophosphorylation of IR/IGF-1R, and activity of ERK1/2 and Akt pathways, serum starvation (24 h in fresh medium without FBS) diminished the Akt Ser473 and Thr308 phosphorylation to ,20% of basal. In serum-starved PSC, insulin at 100 nM induced peak stimulation of Akt phosphorylation that remained elevated at levels of 5-8 fold above basal from 10 min to at least 1 h. IGF-1 at 10 nM also produced peak stimulation, maximally at 10 min. Whereas the basal level of ERK1/2 phosphorylation was high even in serum-starved cells, stimulation with either 100 nM insulin or 10 nM IGF-1 produced transient increases which peaked at approximately 3 min. Interestingly, we also found effects of different culture conditions on mRNA and protein expression of IR/IGF-1R β subunits. In particular, in cells grown to 50% confluence and then shifted to physiologic glucose level (5 mM), marked enhancement of IGF-1R expression levels was exhibited within 24 h, as assessed by Western blot analysis. Also under these conditions, ihPSC express galectin-1, galectin-3 and IGF-1 ligand, and insulin/IGF-1 stimulation enhanced fibronectin production. Interestingly, whereas low glucose was associated with a sustained enhancement in IR/IGF-1R β subunit as well as IGF-1 mRNA expression, exposure to a hyperglycemic condition (25 mM glucose) with or without insulin appeared to destabilize these mRNA and protein expression levels. Conclusions: our data support a role of insulin/IGF-1 in PSC proliferative and profibrotic signaling and suggest that hyperglycemia/ hyperinsulinemia negatively modulate responsiveness to, as well as production of, IGF-1 in PSC.

  • critical residues in the transmembrane helical bundle domains of the human Motilin Receptor for erythromycin binding and activity
    Regulatory Peptides, 2013
    Co-Authors: Sachiko Utsunomiya, Bunzo Matsuura, Teruki Miyake, Masanori Abe, Yoshiou Ikeda, Yoichi Hiasa, Teruhisa Ueda, Shinya Furukawa, Teru Kumagi, Morikazu Onji
    Abstract:

    The Motilin Receptor belongs to a family of Class I G protein-coupled Receptors, and is an important endogenous regulator of gastrointestinal motor function. Motilin and erythromycin, two chemically distinct full agonists of the Motilin Receptor, are known to bind to distinct regions of this Receptor, based on previous systematic mutagenesis of extracellular regions that dissociated the effects on these two agents. The action of these different chemical classes of agonists likely yields a common activation state of the cytosolic face of this Receptor that is responsible for interaction with its G protein. In the current work, we studied the predicted transmembrane (TM) domains of this Receptor for functional responses to Motilin and erythromycin. Motilin Receptor constructs were prepared in which each residue in the TM domains was mutated to alanine or valine. Each construct was expressed in COS cells and characterized for Motilin and erythromycin binding and intracellular calcium responses stimulated by both agonists. Constructs with mutations of residues, Asp94, Leu95, Arg97 and Trp99 in TM2, Ser169 in TM4, and Tyr321 and Glu325 in TM6, were responsible for the negative impact on biological activity stimulated by erythromycin, but had no effect on Motilin responses. On the other hand, constructs with mutations of residues, Leu113 in TM3, Pro172 in TM4, Trp250 and Tyr255 in TM5, and Gln334 in TM7, were negatively responsive to both erythromycin and Motilin. These data support important roles of new regions in the TM domains of the Motilin Receptor for erythromycin action, suggesting differential mechanisms of actions by peptidyl and non-peptidyl ligands.

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  • stimulatory action of mitemcinal gm 611 an acid resistant non peptide Motilin Receptor agonist on colonic motor activity and defecation spontaneous and mitemcinal induced giant migrating contractions during defecation in dogs
    Neurogastroenterology and Motility, 2009
    Co-Authors: Takeshi Hirabayashi, Yasuhide Morikawa, Hiroshi Matsufuji, Ken Hoshino, K Hagane, Kenichi Ozaki
    Abstract:

    The aim of this study was to characterize giant migrating contractions (GMCs) during spontaneous defecation in dogs and to investigate the effect of mitemcinal (an orally active and highly acid-resistant Motilin Receptor agonist) on colonic motility to assess the possibility of using it for the treatment of colonic motility disorders. To assess colonic motility, strain-gauge force transducers were implanted on the gastrointestinal tract of five dogs, and the behaviour of the dogs was monitored with a noctovision-video camera system. The effect of mitemcinal (0, 3, 10 or 30 mg per dog) and sennoside (300 mg per dog) on colonic motility was assessed 24 h after oral administration. During a 39-day period, the starting point of most of the 140 GMCs was between the transverse colon and the descending colon, but some variation was observed. In the daytime, the GMCs originated from somewhat more proximal positions than at night. Mitemcinal caused an increase in the GMC-index (integration of contractile amplitude and duration) and proximal translocation of the GMC starting point, but did not cause an increase in the number of defecations 12 h after administration. Sennoside, however, caused a significant increase in the number of defecations, an increase in the GMC-index, and prolongation of the duration of GMCs. The GMC starting point in the canine colon varied during spontaneous defecation. Mitemcinal was a potent prokinetic drug to mimic a spontaneous defecation compared with sennoside. Mitemcinal evacuates more intestinal luminal contents during the defecation than does sennoside.

  • an orally active Motilin Receptor antagonist ma 2029 inhibits Motilin induced gastrointestinal motility increase in fundic tone and diarrhea in conscious dogs without affecting gastric emptying
    European Journal of Pharmacology, 2009
    Co-Authors: Kenichi Ozaki, Hirokazu Sudo, Hiroyasu Muramatsu, Kenji Yogo, Kenshi Kamei, Shoshin Yoshida, Mitsu Onoma, Osamu Cynshi, Rie Shiokawa, Osamu Kuromaru
    Abstract:

    Abstract The pharmacological properties of MA-2029, a selective and competitive Motilin Receptor antagonist, were investigated in conscious dogs after oral administration. Gastrointestinal contractile activity was recorded by chronically implanted force transducers. The proximal gastric volume was measured with a barostat under constant pressure. Gastric emptying was examined using the paracetamol absorption test. MA-2029 (0.3–10 mg/kg, p.o.) administered in the interdigestive state inhibited gastrointestinal contractions induced by Motilin (3 µg/kg, i.v.) in a dose-dependent manner. MA-2029 (0.3–3 mg/kg, p.o.) also inhibited the occurrence of spontaneous phase III contractions, even though MA-2029 had no effect on basal gastrointestinal motility or basal gastric emptying even at 10 and 30 mg/kg p.o. The inhibitory effect of MA-2029 on Motilin-induced gastrointestinal motility corresponded to its plasma concentration. Motilin (0.3 µg/kg/h, i.v. infusion) reduced the proximal gastric volume by about 50% of control during isobaric distension. This effect was also inhibited by MA-2029 (1–10 mg/kg, p.o.) in a dose-dependent manner. In the digestive state, injection of Motilin (3 µg/kg, i.v.) induced diarrhea in 9 of 11 dogs. MA-2029 (1–30 mg/kg, p.o.) reduced the incidence of diarrhea induced by Motilin in a dose-dependent manner. The results indicate that MA-2029 inhibits hypermotility induced by Motilin in conscious dogs without having an effect on the basal gastrointestinal tone or gastric emptying rate. MA-2029 may be useful in treating gastrointestinal disorders in which the pathogenesis involves the elevation of circulating Motilin.

  • mitemcinal gm 611 an orally active Motilin Receptor agonist improves delayed gastric emptying in a canine model of diabetic gastroparesis
    Clinical and Experimental Pharmacology and Physiology, 2008
    Co-Authors: Mitsu Onoma, Kenichi Ozaki, Hiroyasu Muramatsu, Kenji Yogo, Kenshi Kamei, Makoto Monnai, Yoshiki Kawabe, Shuji Hayashi, Toshihiko Shiga, Saori Matsuo
    Abstract:

    SUMMARY 1 The aim of the present study was to evaluate the effects of mitemcinal (GM-611), an orally active Motilin Receptor agonist, on delayed gastric emptying in a canine model of diabetic gastroparesis and to compare these effects with those of cisapride. 2 Moderate hyperglycaemia was induced by a single intravenous injection of a mixture of streptozotocin (30 mg/kg) and alloxan (50 mg/kg). Dogs that maintained moderate hyperglycaemia (fasting plasma glucose 200–300 mg/dL) without insulin treatment were selected and gastric emptying in these dogs was determined by the paracetamol method. 3 One year after the onset of diabetes, there was no difference in the gastric emptying of normal and diabetic dogs. However, after 5 years, the diabetic dogs showed delayed gastric emptying. The motor nerve conduction velocity of the tibial nerve was significantly lower in diabetic dogs comapred with normal dogs at both time points. 4 Histopathological examination at the end of the study showed that there were fewer nerve fibres in both dorsal vagal and tibial nerves of diabetic dogs comapred with normal dogs. The onset of delayed gastric emptying is thought to have occurred gradually, in parallel with abnormal autonomic nerve function induced by the long period of moderate hyperglycaemia. 5 Oral administration of mitemcinal (0.125, 0.25 or 0.5 mg/kg) dose-dependently accelerated delayed gastric emptying, significant at 0.5 mg/kg, in diabetic dogs, whereas cisapride (1, 3 or 10 mg/kg) had no significant effect. These results add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis.

  • oral administration of ma 2029 a novel selective and competitive Motilin Receptor antagonist inhibits Motilin induced intestinal contractions and visceral pain in rabbits
    European Journal of Pharmacology, 2008
    Co-Authors: Hirokazu Sudo, Kenichi Ozaki, Hiroyasu Muramatsu, Kenji Yogo, Kenshi Kamei, Shoshin Yoshida, Mitsu Onoma, Osamu Cynshi, Osamu Kuromaru, Theo L. Peeters
    Abstract:

    Abstract The pharmacological properties of MA-2029, a novel Motilin Receptor antagonist, were investigated. In vitro , MA-2029 (1 to 30 nM) competitively inhibited Motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA 2 value of 9.17 ± 0.01 ( n  = 5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 μM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [ 125 I]Motilin to Motilin Receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human Motilin Receptors. The p K i of MA-2029 was 8.58 ± 0.04 in the rabbit colon homogenate ( n  = 4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo , orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by Motilin (3 μg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of Motilin (3 μg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive Motilin Receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.

  • effects of mitemcinal gm 611 an acid resistant nonpeptide Motilin Receptor agonist on the gastrointestinal contractile activity in conscious dogs
    Pharmacology, 2007
    Co-Authors: Kenichi Ozaki, Zen Itoh, Hirokazu Sudo, Kenji Yogo, Kenshi Kamei, Hiroshi Koga, Satoshi ōmura, Mitsu Onoma, Michitaka Akima, Hisanori Takanashi
    Abstract:

    The effects of mitemcinal (GM-611) on the gastrointestinal contractile activity were investigated using chronically implanted force transducers in conscious dogs and were compared with the effects of porcine Motilin (pMTL), EM-523 and EM-574. In the interdigestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 induced the gastrointestinal contractile activity in a manner similar to pMTL. The contractile activity caused by mitemcinal was suppressed by continuous intravenous infusion of a Motilin Receptor antagonist. In the digestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 also stimulated the gastrointestinal contractile activity. Mitemcinal, EM-523 and EM-574 given intravenously increased the gastric contractile activity in a similar dose range; however, mitemcinal was approximately 10 times more potent than EM-523 and EM-574 when administered orally in the digestive state. These results indicate that the mitemcinal-induced gastrointestinal contractile activity operates via Motilin Receptors and possesses a higher activity than EM-523 and EM-574 when administered orally in conscious dogs in the digestive state. Mitemcinal may therefore be useful in the treatment of several gastrointestinal disorders involving dysmotility, such as gastroparesis and functional dyspepsia, even when administered orally.