Metabotropic Glutamate Receptor Subtypes as Targets for Neuroprotective Drugs

@article{Bruno2001MetabotropicGR,
  title={Metabotropic Glutamate Receptor Subtypes as Targets for Neuroprotective Drugs},
  author={Valeria Bruno and Giuseppe Battaglia and Agata Copani and Mara D'Onofrio and Patrizia Di Iorio and Antonio de Blasi and Daniela Melchiorri and Peter Josef Flor and Ferdinando Nicoletti},
  journal={Journal of Cerebral Blood Flow \& Metabolism},
  year={2001},
  volume={21},
  pages={1013 - 1033}
}
Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2… 

Metabotropic glutamate receptors in neurodegeneration/neuroprotection: Still a hot topic?

Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP.

In vivo and in vitro characterization of the newer mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) indicates that it is more highly selective for mGLUR5 over mGlamR1, has no effect on other mGLuR subtypes, and has fewer off-target effects than MPEP.

Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

The currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson’s disease, Alzheimer's disease and pain is reviewed.

Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status

While mGLU5 receptor negative allosteric modulators have the potential to be protective against convulsive seizures and hyperactivity-induced neurodegeneration, drugs that enhance mGlu5 andmGlu7 receptor function may have beneficial effects in the treatment of absence epilepsy.

Group II Metabotropic Glutamate Receptors (mGlu2 and mGlu3)

Emerging preclinical results with mGlu2/3 antagonists and potentiators of the mGLU2 receptor indicate that, despite a presynaptic localization distal to the synaptic active zone, significant glutamatergic tone can occur under some physiologic conditions.

The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

It is concluded that neuroprotection bymGlu2/3 receptor agonists requires the activation of astrocytic mGlu3 receptors, whereas, unexpectedly, activation of mGLU2 receptors might be harmful to neurons exposed to toxic insults.

Activation of mGlu3 Receptors Stimulates the Production of GDNF in Striatal Neurons

It is speculated that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.

A Role for Noradrenergic Transmission in the Actions of Phencyclidine and the Antipsychotic and Antistress Effects of mGlu2/3 Receptor Agonists

Data support a role for noradrenergic neurotransmission in the actions of drugs such as phencyclidine and suggest that stress pathways associated with these drugs can be normalized by mGlu2/3 receptor activation.
...

References

SHOWING 1-10 OF 212 REFERENCES

Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective

BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity.

BAY36-7620 will be useful to further delineate the functional importance of the mGlu1 receptor, including its putative agonist-independent activity, andTransmembrane helices 4 to 7 are shown to play a critical role in the selectivity of BAY36- 7620.

Selective Blockade of Type-1 Metabotropic Glutamate Receptors Induces Neuroprotection by Enhancing Gabaergic Transmission

Results indicate that selective blockade of mGlu1 receptors produces neuroprotection by enhancing inhibitory postsynaptic currents in GABAergic transmission.

Selective mGluR5 antagonists MPEP and SIB‐1893 decrease NMDA or glutamate‐mediated neuronal toxicity through actions that reflect NMDA receptor antagonism

The neuroprotective effects of these compounds are most likely mediated through their NMDA receptor antagonist action, and caution should be exercised when drawing conclusions about the roles of mGluR5 based on their use.

Pharmacological agents acting at subtypes of metabotropic glutamate receptors

The role of metabotropic glutamate receptor (mGluR) ligands in parkinsonian muscle rigidity

It is suggested that stimulation of group II striatal mGluRs seems to play a major role in diminution of parkinsonian-like muscle rigidity, however, it seems that the antagonism of group I mGLURs located in the nucleus accumbens may also be of importance to the antiparkinsonian effect.

Selective Activation of mGlu4 Metabotropic Glutamate Receptors Is Protective against Excitotoxic Neuronal Death

Microdialysis studies showed that intrastriatal infusion of NMDA increased extracellular glutamate levels to a greater extent in −/− than in +/+ mice, supporting the hypothesis that the mGluR4 subtype is necessary for the maintenance of the homeostasis of extrace cellular glutamate levels.

A novel, competitive mGlu5 receptor antagonist (LY344545) blocks DHPG‐induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices

The identification of LY344545 as the first competitive antagonist to show selectivity towards mGlu5 receptors supports the potential to design more selective and potent competitive antagonists of this receptor and indicates that mGLU receptor‐mediated potentiation of NMDA responses is not essential for the induction of LTP.
...