Transient lower esophageal sphincter relaxations in dogs are inhibited by a metabotropic glutamate receptor 5 antagonist

Jensen, Jörgen; Lehmann, Anders; Uvebrant, Anna; Carlsson, Anita; Jerndal, Gunilla; Nilsson, Karolina; Frisby, Claudine L.; Blackshaw, L. Ashley; Mattsson, Jan P.

doi:10.1016/j.ejphar.2005.07.007

Cited by 59 publications

(41 citation statements)

References 18 publications

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“…114,115 These findings suggested a potential thera-peutic role for mGluR5 antagonists in the treatment of GERD. Recently, the effects of the mGluR5 antagonist on oesophageal acid exposure in humans were assessed and a decrease in oesophageal acid exposure after receiving an mGluR5 antagonist was observed.…”

Section: Mglur5 Receptor Modulatorsmentioning

confidence: 99%

Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease

Kessing

Conchillo

Bredenoord

et al. 2011

Alimentary Pharmacology &Amp; Therapeutics

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Section: Mglur5 Receptor Modulatorsmentioning

confidence: 99%

Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease

Kessing

Conchillo

Bredenoord

et al. 2011

Alimentary Pharmacology &Amp; Therapeutics

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“…In ferrets, the mGluR-5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and the more specific compound 3-(2-methyl-4-thiazolyl)ethynyl-pyridine (MTEP) have been shown to dose-dependently inhibit TLESR, reduce reflux episodes, and increase basal LES pressure, while the group II and III agonists were relatively ineffective [22]. Similarly, a reduction in TLESR and reflux episodes were also demonstrated in dogs using MPEP [39]. In rats, MTEP has been shown to inhibit mechanically evoked visceral nociception [40•], implicating the involvement of mGluR-5 receptors and the potential sensory modification property of GluR5 receptor antagonists.…”

Section: Mglur Antagonistsmentioning

confidence: 83%

Beyond Acid Suppression: New Pharmacologic Approaches for Treatment of GERD

Kuo

Holloway

2010

Curr Gastroenterol Rep

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Proton pump inhibitors are highly successful in treating gastroesophageal reflux disease, but a significant proportion of patients have persistent symptoms from weakly or nonacidic reflux. Transient lower esophageal sphincter relaxation (TLESR) represents the dominant mechanism of gastroesophageal reflux and has therefore become the most intensely investigated therapeutic target. The triggering of TLESR involve the vagal pathways and the gamma-aminobutyric type B (GABA(B)) and metabotropic glutamate type 5 (mGluR5) receptors. Baclofen is a GABA(B) receptor agonist that is effective in inhibiting TLESR and reducing the number of reflux episodes, but is associated with significant central nervous system (CNS) side effects. The newer GABA(B) agonists, such as AZD9343 and AZD3355, and mGluR5 antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP), have been shown in small, randomized, controlled trials to have comparable efficacy to baclofen, but possibly a more favorable CNS side effect profile. Cannibinoid agonists, such as Delta(9)-THC, have also been demonstrated to reduce TLESRs and reflux events respectively. Macrolide antibiotics (eg, erythromycin) show early promise in a select group of patients with possible reflux associated post-lung transplant problems.

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“…Other GABA B agonists with supposed improved tolerability are currently in development and data from clinical studies of these agents in GERD patients are awaited with interest. Metabotropic glutamate receptor 5 (mGluR5) antagonists also represent a very promising class of compounds which has been shown to reduce TLESRs and reflux in dogs [26] and ferrets [27]. The rationale for this effect is that glutamate mediates slow pre-and post-synaptic neurotransmission and modulation within the CNS; moreover, the transmission of signals from vagal afferent terminals in the NTS is mainly glutamatergic.…”

Section: Pharmacological Control Of Tlesrsmentioning

confidence: 98%

Pharmacological treatment of GERD – a look beyond PPIs?

Zerbib

2009

Eur Surg

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Zusammenfassung. Grundlagen: Etwa 20-30% der Patienten mit gastroösophagealer Refluxkrankheit haben immer noch Beschwerden, trotz Therapie mit einem Protonenpumpenhemmer (PPI). Bei diesen Patienten können in 40-50% der Fälle auch unter PPI-Therapie saure und nicht saure Refluxe nachgewiesen werden und somit die Therapie nicht voll ausgeschöpft erscheint. Transiente Erschlaffungen des LES (TLESRs) sind die Ursache für Refluxe. Deshalb bieten die TLESRs einen zusätzlichen therapeutischer Ansatz in der GERD-Therapie.Methodik: Ü bersicht zur medikamentösen Therapie der TLESRs.Ergebnisse: Unter den Medikamenten, welche die TLESRs hemmen, ist der GABA B -Agonist Baclofen der vielversprechendste Ansatz, da er durch Hemmung der Säureexposition der Speiseröhre die Beschwerden lindert. Auch ADX10059, ein mGluR5-Antagonist, zeigt Wirksamkeit in der GERD-Therapie. Limitierend sind derzeit noch die Nebenwirkungen wie Ü belkeit, Erbrechen und Schwindel, welche durch ein entsprechendes Drug Design ausgeräumt werden sollten.Schlussfolgerungen: Substanzen, welche die TLESRs hemmen, stellen einen vielversprechenden neuen Ansatz in der GERD Therapie dar.Schlüsselwörter: Gastroesophagealer Reflux, Baclofen, GERD, Protonenpumpenhemmer, Manometrie, pHMetrie. Summary.Background: Approximately 20-30% of patients with gastro-esophageal reflux symptoms report inadequate symptom relief while on PPI therapy. Persisting acid or nonacid reflux can be demonstrated in 40-50% of them suggesting that there is room for anti-reflux therapy in these patients. Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism of all type of reflux, i.e. both acid and weakly acidic reflux episodes. Therefore, controlling the occurrence of TLESRs appears to be a relevant therapeutic objective in GERD.Methods: Review on the pharmacological therapy of TLESRs for GERD management.Results: Many compounds have been shown to decrease the number of TLESRs, but the most promising classes are GABA B agonists and mGluR5 antagonists both of which have orally formulations available for human use. The GABA B agonist baclofen, prescribed for the treatment of spasticity for many years, has been shown to decrease the number of TLESRs, esophageal acid exposure, and reflux symptoms. Considering the poor tolerability of this compound, more selective GABA B agonists are currently in development. ADX10059, a mGluR5 negative allosteric modulator, has been shown to decrease GER in both healthy subjects and GERD patients and has entered in phase IIb studies.Conclusions: Compounds that target TLESR activity represent a promising new therapeutic option for patients who suffer from GERD symptoms. These drugs will probably be developed as add-on therapy in combination with PPIs provided the tolerability and safety issues are resolved.

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Transient lower esophageal sphincter relaxations in dogs are inhibited by a metabotropic glutamate receptor 5 antagonist

Cited by 59 publications

References 18 publications

Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease

Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease

Beyond Acid Suppression: New Pharmacologic Approaches for Treatment of GERD

Pharmacological treatment of GERD – a look beyond PPIs?

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