Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1-10 microM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001-10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit.
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PMID:Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5. 1705 58

Gastro-oesophageal reflux disease (GORD) is caused by disordered control of the gastro-oesophageal reflux barrier, comprised internally of the lower oesophageal sphincter (LOS) and externally the crural diaphragm (CD). Both relax briefly to allow bolus passage during oesophageal peristalsis. Brief relaxation also occurs prior to gastro-oesophageal reflux, known as transient LOS relaxation (TLOSR), normally allowing venting of gas. TLOSRs also account for up to 90% of acid reflux episodes. The development of GORD therefore depends upon the rate of TLOSR and the physical and chemical nature of refluxate. We established an animal model of reflux in ferrets, in which similar patterns of TLOSR are seen to humans. TLOSRs are mediated via a vago-vagal pathway initiated by tension receptors in the gastric musculature. They have central terminals in the brainstem which provide input to a central program generator. The program has 3 simultaneous outputs: 1. brief activation of vagal motor neurones to the LOS, which activate inhibitory enteric motorneurones, leading to smooth muscle relaxation: 2. suppression of oesophageal peristalsis: 3. suppression of motor output to the CD. We have investigated several aspects of the TLOSR pathway in ferrets, and determined that the optimal site for therapeutic pharmacological intervention is at gastric vagal tension receptor endings. Their responses to distension are potently inhibited by gamma-aminobutyric acid type B (GABAB) receptor agonists and metabotropic glutamate type 5 receptor (mGluR5) antagonists. These effects translate to inhibition of TLOSR and reflux in animal models and humans. Clinical studies indicate both types of drug may have potential in the treatment of GORD.
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PMID:New insights in the neural regulation of the lower oesophageal sphincter. 1892 42

Proton pump inhibitors (PPIs) are very effective and safe drugs for the treatment of erosive and non-erosive gastroesophageal reflux disease (GERD). Nevertheless, a significant proportion of GERD patients (30 - 40%) continue to suffer from symptoms during PPI treatment, which has stimulated the search for better drugs. Improvement of PPI pharmacokinetics and pharmacodynamics has been the main focus of drug development in the past decade with the ultimate goal of optimizing acid inhibition. New inhibitors of the proton pump with a longer half-life, acting faster and longer, have been developed, including potassium-competitive acid blockers. Recent data, however, suggest that the therapeutic efficacy of acid suppression may have reached its maximum and other mechanisms may have to be targeted to further improve symptom control. Potential drugs interacting with different targets are reflux inhibitors such as GABA(B) receptor agonists and mGluR5 antagonists. These agents reduce the number of transient lower esophageal sphincter relaxation thereby reducing both acid and non-acid reflux. Theoretically, visceral analgesics to modulate visceral perception or even growth factors to enhance mucosal healing may be other emerging drugs to treat GERD.
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PMID:Emerging drugs for gastroesophageal reflux disease. 1965 Jul 46

Metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) have previously been implicated in a number of pathophysiological conditions, based on preclinical, and to some extent clinical, proof of concept for migraine, gastroesophageal reflux disease, Parkinson's disease and anxiety. In the past, the potential use of known mGlu5 antagonists for the treatment of lower urinary tract disorders was disclosed. In the patent evaluated herein, novel derivatives of 4-(prop-2-ynylidene)piperidine are described and claimed by Recordati Ireland Ltd, Ireland, as NAMs at mGlu5 for the treatment of lower urinary tract disorders. Selected compounds reported in this application were efficacious in the cystometry model of bladder dysfunction in conscious rats, and mGlu5 NAMs are, therefore, suggested to have potential for the treatment of lower urinary tract disorders.
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PMID:Novel heterocyclic compounds as mGlu5 antagonists: WO2009015897. 2018 Jun 23

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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PMID:Beyond acid suppression: new pharmacologic approaches for treatment of GERD. 2042 77

Approximately 20-30% of patients with gastro-oesophageal reflux symptoms report inadequate symptom relief while on PPI therapy. Persisting acid or non-acid reflux can be demonstrated in 40-50% of them suggesting that there is room for anti-reflux therapy in these patients. New anti-reflux compounds aim at decreasing the occurrence of transient lower oesophageal sphincter relaxations (TLOSRs) which represent the main mechanism of all types of reflux. The most promising classes of compounds are GABA(B) agonists and mGluR5 antagonists which have been shown to reduce both reflux episodes and symptoms and are currently under evaluation in phase II and III clinical trials. Compounds that target TLOSR activity represent a promising new therapeutic option for patients who suffer from GORD 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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PMID:Medical treatment of GORD. Emerging therapeutic targets and concepts. 2112 5

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson's disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability to enhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.
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PMID:Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders. 2136 21

Metabotropic glutamate receptors (mGluR) have a diverse range of structures and molecular coupling mechanisms. There are eight mGluR subtypes divided into three major groups. Group I (mGluR1 and 5) is excitatory; groups II (mGluR2 and 3) and III (mGluR 4, 6, and 7) are inhibitory. All mGluR are found in the mammalian nervous system but some are absent from sensory neurons. The focus here is on mGluR in sensory pathways from the viscera, where they have been explored as therapeutic targets. Group I mGluR are activated by endogenous glutamate or constitutively active without agonist. Constitutive activity can be exploited by inverse agonists to reduce neuronal excitability without synaptic input. This is promising for reducing activation of nociceptive afferents and pain using mGluR5 negative allosteric modulators. Many inhibitory mGluR are also expressed in visceral afferents, many of which markedly reduce excitability. Their role in visceral pain remains to be determined, but they have shown promise in inhibition of the triggering of gastro-esophageal reflux, via an action on mechanosensory gastric afferents. The extent of reflux inhibition is limited, however, and may not reach a clinically useful level. On the other hand, negative modulation of mGluR5 has very potent actions on reflux inhibition, which has produced the most likely candidates so far as therapeutic drugs. These act probably outside the central nervous system, and may therefore provide a generous therapeutic window. There are many unanswered questions about mGluR along visceral afferent pathways, the answers to which may reveal many more therapeutic candidates.
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PMID:Metabotropic glutamate receptors as novel therapeutic targets on visceral sensory pathways. 2147 28