Metabotropic glutamate receptor 5

Function

The amino acid L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacological properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7, and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Alternative splice variants of GRM8 have been described but their full-length nature has not been determined.

There has been extensive research into the role of mGluR5 in psychological disorders, such as addiction and anxiety. Emerging research strongly points to mGluR5 playing a direct role in the pathogenesis of alcohol use disorder in humans, showing intimate involvement in the development of behavioral sensitization towards ethanol in animal models.

Ligands

In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinct allosteric binding sites exist on the mGluR5. A respectable number of potent and selective mGluR5 ligands, which also comprise PET radiotracers, has been developed to date. Selective antagonists and negative allosteric modulators of mGluR5 are a particular area of interest for pharmaceutical research, due to their demonstrated anxiolytic, antidepressant and anti-addictive effects in animal studies and their relatively benign safety profile. mGluR5 receptors are also expressed outside the central nervous system, and mGluR5 antagonists have been shown to be hepatoprotective and may also be useful for the treatment of inflammation and neuropathic pain. The clinical use of these drugs may be limited by side effects such as amnesia and psychotomimetic symptoms, but these could be an advantage for some indications, or conversely mGluR5 positive modulators may have nootropic effects.

Agonists

• CHPG (2-amino-2-(2-chloro-5-hydroxyphenyl)acetic acid)
• Monellin
• Glutamate

Antagonists

• Lithium
• LY-344,545
• Mavoglurant
• Remeglurant
• SIB-1893
• (RS)-MCPG

Positive allosteric modulators

• ADX-47273
• CPPHA
• VU-29: Ki = 244 nM, EC50 = 9.0 nM; VU-36: Ki = 95 nM, EC50 = 10.6 nM
• VU-1545: Ki = 156 nM, EC50 = 9.6 nM
• CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide)
• DFB (1-(3-fluorophenyl)-N-((3-fluorophenyl)methylideneamino)methanimine)

Negative allosteric modulators

• AZD9272
• Basimglurant
• Dipraglurant
• Fenobam
• GRN-529
• MPEP
• MTEP: more potent than MPEP
• Raseglurant
• VU0424238 (Tamagnan's name)
• GET73 (Fluvoxamine/Zafuleptine) type analog used to treat anxiety and alcoholism.

mGluR5 and addiction

Mice with a knocked out mGluR5 show a lack of cocaine self-administration regardless of dose. This suggested that the receptor may be intimately involved in integrating the rewarding properties of cocaine. However, a later study showed that mGluR5 knockout mice responded the same to cocaine reward as wild type mice demonstrated by a cocaine place-preference paradigm. This evidence taken together shows that mGluR5 may be crucial for drug-related instrumental self-administration learning, but not conditioned associations.

References

References

1. (October 2000). "Quisqualate induces an inward current via mGluR activation in neocortical pyramidal neurons". Brain Research.
2. (October 1997). "Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus". The Journal of Neuroscience.
3. (March 1994). "Molecular cloning and the functional expression of two isoforms of human metabotropic glutamate receptor subtype 5". Biochemical and Biophysical Research Communications.
4. "Entrez Gene: GRM5 glutamate receptor, metabotropic 5".
5. (2012). "mGlu5 Receptor Functional Interactions and Addiction". Frontiers in Pharmacology.
6. (2021). "mGlu5: A double-edged sword for aversive learning related therapeutics". Neuroanatomy and Behaviour.
7. (March 2008). "N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors". Molecular Pharmacology.
8. (January 2006). "The glutamate story". British Journal of Pharmacology.
9. (March 2009). "mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats". Neuropsychopharmacology.
10. (April 2006). "Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking". Neuropsychopharmacology.
11. (2005). "Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats". Neuropharmacology.
12. (2005). "Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications". Current Topics in Medicinal Chemistry.
13. (September 2008). "mGluR5 antagonists: discovery, characterization and drug development". Current Opinion in Drug Discovery & Development.
14. (January 2009). "The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception". Neuroscience Letters.
15. (May 2009). "Selective blockade of mGlu5 metabotropic glutamate receptors is hepatoprotective against fulminant hepatic failure induced by lipopolysaccharide and D-galactosamine in mice". Journal of Applied Toxicology.
16. (Jul 2005). "The role of metabotropic glutamate receptor 5 in learning and memory processes". Drug News & Perspectives.
17. (November 2005). "The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity". Cerebral Cortex.
18. (July 2007). "Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs". Pharmacology & Therapeutics.
19. (August 2008). "MGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats". Behavioural Brain Research.
20. (March 2009). "mGluR5 has a critical role in inhibitory learning". The Journal of Neuroscience.
21. (August 2009). "mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning". Neuropsychopharmacology.
22. Chen ANY, Hellyer SD, Trinh PNH, Leach K, Gregory KJ (2019): Identification of monellin as the first naturally derived proteinaceous allosteric agonist of metabotropic glutamate receptor 5. ''Basic Clin Pharmacol Toxicol.'' PMID 30983151
23. (2011). "Autism Spectrum Disorders". Oxford University Press.
24. (December 2008). "ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities". The Journal of Pharmacology and Experimental Therapeutics.
25. (March 2007). "Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA". Bioorganic & Medicinal Chemistry Letters.
26. (May 2004). "A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain". The Journal of Pharmacology and Experimental Therapeutics.
27. (May 2007). "Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses". Molecular Pharmacology.
28. (June 2006). "Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes". Journal of Medicinal Chemistry.
29. (April 2005). "A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models". The Journal of Pharmacology and Experimental Therapeutics.
30. (November 2012). "Discovery and characterization of AZD9272 and AZD6538-Two novel mGluR5 negative allosteric modulators selected for clinical development". Bioorganic & Medicinal Chemistry Letters.
31. (April 2012). "Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism". Science Translational Medicine.
32. (June 2017). "Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation". Journal of Medicinal Chemistry.
33. (September 2001). "Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice". Nature Neuroscience.
34. (August 2011). "mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine". Nature Precedings.