Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The globus pallidus (GP) is a key GABAergic nucleus in the basal ganglia (BG). The predominant input to the GP is an inhibitory striatal projection that forms the first synapse in the indirect pathway. The GP GABAergic neurons project to the subthalamic nucleus, providing an inhibitory control of these glutamatergic cells. Given its place within the BG circuit, it is not surprising that alterations in GP firing pattern are postulated to play a role in both normal and pathological motor behavior. Because the inhibitory striatal input to the GP may play an important role in shaping these firing patterns, we set out to determine the role that the group III metabotropic glutamate receptors (GluRs) play in modulating transmission at the striatopallidal synapse. In rat midbrain slices, electrical stimulation of the striatum evoked GABA(A)-mediated IPSCs recorded in all three types of GP neurons. The group III mGluR-selective agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) inhibited these IPSCs through a presynaptic mechanism of action. L-AP4 exhibited high potency and a pharmacological profile consistent with mediation by mGluR4. Furthermore, the effect of L-AP4 on striatopallidal transmission was absent in mGluR4 knock-out mice, providing convincing evidence that mGluR4 mediates this effect. The finding that mGluR4 may selectively modulate striatopallidal transmission raises the interesting possibility that activation of mGluR4 could decrease the excessive inhibition of the GP that has been postulated to occur in Parkinson's disease. Consistent with this, we find that intracerebroventricular injections of L-AP4 produce therapeutic benefit in both acute and chronic rodent models of Parkinson's disease.
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PMID:Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. 1290 82

Parkinson's disease (PD) is a debilitating movement disorder that afflicts >1 million people in North America. Current treatments focused on dopamine-replacement strategies ultimately fail in most patients because of loss of efficacy and severe adverse effects that worsen as the disease progresses. The recent success of surgical approaches suggests that a pharmacological intervention that bypasses the dopamine system and restores balance in the basal ganglia motor circuit may provide an effective treatment strategy. We previously identified the metabotropic glutamate receptor 4 (mGluR4) as a potential drug target and predicted that selective activation of mGluR4 could provide palliative benefit in PD. We now report that N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is a selective allosteric potentiator of mGluR4. This compound selectively potentiated agonist-induced mGluR4 activity in cultured cells expressing this receptor and did not itself act as an agonist. Furthermore, PHCCC potentiated the effect of l-(+)-2-amino-4-phosphonobutyric acid in inhibiting transmission at the striatopallidal synapse. Modulation of the striatopallidal synapse has been proposed as a potential therapeutic target for PD, in that it may restore balance in the basal ganglia motor circuit. Consistent with this, PHCCC produced a marked reversal of reserpine-induced akinesia in rats. The closely related analogue 7-(hydroxylimino)cyclopropachromen-1a-carboxamide ethyl ester, which does not potentiate mGluR4, had no effect in this model. These results are evidence for in vivo behavioral effects of an allosteric potentiator of mGluRs and suggest that potentiation of mGluR4 may be a useful therapeutic approach to the treatment of PD.
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PMID:Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. 1459 2

Glutamate plays an important role in the regulation of dopamine neuron activity. In particular, the glutamatergic input from the subthalamic nucleus is thought to provide control over dopamine neuron firing patterns. The degeneration of dopamine neurons in the substantia nigra pars compacta (SNc) observed in Parkinson's disease (PD) is believed to be due to a complex interplay of factors, including oxidative stress and mitochondrial dysfunction. Although glutamate is not the primary cause of cell death in PD, there is evidence suggesting excessive glutamate release onto dopamine neurons may play a role in continued degeneration. Although many studies have focused on the role of glutamate in the SNc, little work has been directed at exploring the modulatory control of glutamate release in this region. Previous studies have found a high-potency inhibitory effect of nonselective group III mGluR agonist on glutamatergic transmission in the SNc. Using whole-cell patch-clamp methods and novel pharmacological tools, we have determined that mGluR4 mediates the group III mGluR modulation of excitatory transmission in the rat SNc. The group III mGluR-selective agonist l-(+)-2-amino-4-phosphonobutyric acid inhibits excitatory transmission in the SNc at low micromolar concentrations with a maximal inhibition occurring at 3 muM. This effect was potentiated by the mGluR4-selective allosteric modulator N-phenyl-7-(hydroxymino)cyclopropa[b]chromen-1a-carboxamide and was not mimicked by the mGluR8-selective agonist (S)-3,4-dicarboxyphenylglycine. Interestingly, in an attempt to employ knockout mice to confirm the role of mGluR4, we discovered an apparent species difference suggesting that in mice, both mGluR4 and mGluR8 modulate excitatory transmission in the SNc.
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PMID:Group III metabotropic glutamate-receptor-mediated modulation of excitatory transmission in rodent substantia nigra pars compacta dopamine neurons. 1576 Nov 15

Positive allosteric modulators of metabotropic glutamate receptors (mGluRs) are the subject of intensive research due to their emerging therapeutic potential for a range of psychiatric and neurological disorders such as pain, anxiety, cognition, Parkinson's disease and schizophrenia. Positive allosteric modulators, which are small molecules capable of enhancing agonist-mediated receptor activity while possessing no intrinsic agonist activity, have recently been described for group I (mGluR1 and mGluR5), group II (mGluR2) and group III (mGluR4) mGluRs. Relative to classical mGluR agonists, these molecules offer improved selectivity versus other mGluRs and chemical tractability, and may reduce the liability of receptor desensitization.
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PMID:Recent advances in positive allosteric modulators of metabotropic glutamate receptors. 1602 81

Over the last several years a great deal of interest has been focused on the metabotropic glutamate receptors as potential targets for the treatment of a variety of disorders of the central nervous system. Recently, selective agonist or allosteric potentiators of mGluR4, one of the group III mGluRs, have been proposed as potential novel therapeutics for the palliative treatment of Parkinson's disease and some forms of epilepsy. mGluR4 stands out amongst the group III mGluRs due to its relatively restricted localization and apparent role in several key neuronal circuits. Work from a number of laboratories has led to the development of more selective tools for the study of mGluR4, as well as refined models of the structure and function of this receptor. In addition, a growing body of literature suggests that mGluR4 plays a key neuroprotective role in broad spectrum of neurodegenerative disorders. It is hoped that this increased understanding of the role of mGluR4 combined with more detailed structural information will spur the development of better pharmacological tools, and ultimately to novel clinical therapy.
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PMID:Targeting the metabotropic glutamate receptor mGluR4 for the treatment of diseases of the central nervous system. 1617 33

Metabotropic glutamate receptors (mGluRs) have been proposed as novel targets for the treatment of a variety of disorders. Recently, highly selective allosteric modulators of the mGluRs have been developed by several groups. These allosteric compounds provide an unprecedented degree of selectivity for individual mGluRs, allowing for more detailed functional studies on the roles of these receptors. Furthermore, the allosteric approach avoids many of the hurdles associated with the development of direct agonists as drugs, and provides a clear path forward for clinical proof-of-concept studies. Currently, both positive allosteric modulators of mGluR2 and negative allosteric modulators of mGluR5 hold promise as novel anxiolytics, and positive allosteric modulators of mGluR4 appear to be an exciting new target for the treatment of Parkinson's disease.
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PMID:Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. 1636 68

Parkinson's disease (PD) is caused by the death of dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia. Activation of metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission in the basal ganglia and results in antiparkinsonian effects in rodent PD models. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is a positive allosteric modulator (PAM) of mGluR4 that has been used to further validate the role of mGluR4 in PD, but the compound suffers from a lack of selectivity, relatively low potency, and poor solubility. Via high-throughput screening, we discovered more than 400 novel PAMs of mGluR4. Compounds derived from a novel chemical scaffold were characterized in vitro at both rat and human mGluR4 using two distinct assays of mGluR4 function. The lead compound was approximately 8-fold more potent than PHCCC, enhanced the potency of glutamate at mGluR4 by 8-fold, and did not show any significant potentiator or antagonist activity at other mGluR subtypes. Resolution of the regioisomers of the lead revealed that the cis regioisomer, (+/-)-cis-2-(3,5-dichlorphenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041), contained the majority of the mGluR4 PAM activity and also exhibited partial agonist activity at mGluR4 at a site that was distinct from the glutamate binding site, suggesting that this compound is a mixed allosteric agonist/PAM of mGluR4. VU0155041 was soluble in an aqueous vehicle, and intracerebroventricular administration of 31 to 316 nmol of VU0155041 dose-dependently decreased haloperidol-induced catalepsy and reserpine-induced akinesia in rats. These exciting results provide continued support for mGluR4 as a therapeutic target in PD.
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PMID:Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. 1866 3

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor and bradykinesia. The primary pathophysiology underlying PD is the degeneration of dopaminergic neurons of the substantia nigra pars compacta. Loss of these neurons causes pathological changes in neurotransmission in the basal ganglia motor circuit. The ability of ionotropic and metabotropic glutamate receptors to modulate neurotransmission throughout the basal ganglia suggests that these receptors may be targets for reversing the effects of altered neurotransmission in PD. Studies in animal models suggest that modulating the activity of these receptors may alleviate the primary motor symptoms of PD as well as side effects induced by dopamine replacement therapy. Moreover, glutamate receptor ligands may slow disease progression by delaying progressive dopamine neuron degeneration. Antagonists of NMDA receptors have shown promise in reversing motor symptoms, levodopa-induced dyskinesias, and neurodegeneration in preclinical PD models. The effects of drugs targeting AMPA receptors are more complex; while antagonists of these receptors exhibit utility in the treatment of levodopa-induced dyskinesias, AMPA receptor potentiators show promise for neuroprotection. Pharmacological modulation of metabotropic glutamate receptors (mGluRs) may hold even more promise for PD treatment due to the ability of mGluRs to fine-tune neurotransmission. Antagonists of mGluR5, as well as activators of group II mGluRs and mGluR4, have shown promise in several animal models of PD. These drugs reverse motor deficits in addition to providing protection against neurodegeneration. Glutamate receptors therefore represent exciting targets for the development of novel pharmacological therapies for PD.
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PMID:Glutamate receptors as therapeutic targets for Parkinson's disease. 1970 65

Although Parkinson's disease was first diagnosed nearly 200 years ago, its effective treatment still remains elusive for most of those diagnosed. The gold standard of treatment for most patients is 3,4-dihydroxy-L-phenylalanine. This drug works for most individuals early in the disease; however, resistant symptoms start to emerge after several years of treatment. There has been increased interest in finding novel therapies to help Parkinson's disease patients. Such strategies may have the benefit of not only treating the symptomatic issues of the disorder, but might also offer promise in protecting dopaminergic neurons from further degeneration. One such target that is now receiving much attention from the scientific community is the metabotropic glutamate receptor mGluR4. In this article, we briefly review Parkinson's disease and then recent work in the mGluR area, with a focus on the efforts being made toward finding and optimizing novel mGluR4 positive allosteric modulators (PAMs). Preclinically in rodent models, mGluR4 activation has offered much promise as a novel treatment of Parkinson's disease. Additionally, the specific use of PAMs, rather than direct-acting agonists at the orthosteric glutamate site, continues to be validated as a viable treatment option for this target. It is anticipated that continued progress in this area will further our understanding of the potential of mGluR4 modulation as a novel symptomatic and potentially disease-modifying treatment for Parkinson's disease.
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PMID:mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease. 2016 43

Stimulation of the metabotropic glutamate receptor 4 (mGluR4) represents a promising new approach to the symptomatic treatment of the neurodegenerative disorder Parkinson's disease (PD). Preclinical models using both agonists and positive allosteric modulators of mGluR4 have demonstrated the potential for this receptor for the treatment of PD. The present article evaluates a recent patent filed by Addex Pharma S.A. claiming a novel series of mGluR4 positive allosteric modulators. Many of the examples disclosed are active at EC(50)'s < 500 nM.
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PMID:mGluR4 positive allosteric modulators with potential for the treatment of Parkinson's disease: WO09010455. 2018 Jun 24


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