4 replies to this topic

[Furniture]

Metabotropic glutamate receptors (mGluR's) are a somewhat newer target of drug development (though they've been discussed on this forum off-and-on for more than a decade now).

 

Antagonizing these receptors (specifically mGluR5 & mGluR1) seems to have profound anxiolytic and anti-convulsant effects with potential to also treat Fragile X syndrome (a genetic condition w/ similarities to autism), drug-induced dyskinesia, Parkinson's disease, OCD, treatment-resistant depression, etc.

 

Metabotropic Glutamate Receptors for Parkinson's Disease Therapy

https://www.hindawi.com/journals/pd/2013/196028/

 

Glutamate metabotropic receptors as targets for drug therapy in epilepsy

https://pubmed.ncbi.nlm.nih.gov/12969743/

 

Metabotropic glutamate receptors as novel targets for anxiety and stress disorders

https://pubmed.ncbi.nlm.nih.gov/15665858/

 

Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome

https://pubmed.ncbi.nlm.nih.gov/25488569/

 

There is a group of medications currently being studied that selectively antagonize (and/or negatively modulate) Metabotropic-glutamate receptors:

 

• Mavoglurant (https://en.wikipedia.org/wiki/Mavoglurant)
• Basimglurant (https://en.wikipedia.org/wiki/Basimglurant)
• Dipraglurant (https://en.wikipedia.org/wiki/Dipraglurant)
• Raseglurant (https://en.wikipedia.org/wiki/Raseglurant)
• Remeglurant (https://en.wikipedia.org/wiki/Remeglurant)

 

However, all of these "-glurant" drugs have either been abandoned during development or are still in the research phase. In other words, none of them are available to the public.

 

That being said, Acamprosate (Campral), a medication used to treat alcohol use disorder & the symptoms of alcohol withdrawal, seems to work, at least partially, via mGluR's.

 

This study used mGluR5 knockout mice & a known mGluR5 antagonist (MPEP) to show that Acamprosate acts on mGluR5:

 

Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: relationship to acamprosate actions

https://pubmed.ncbi.nlm.nih.gov/18377703/

"No effects of acamprosate or MPEP on ethanol-induced LORR and AW were found in mGluR5 knockout mice, demonstrating that mGluR5 is required for these actions. mGluR5 null mutant mice showed decreased alcohol consumption in some, but not all, tests. These data show the importance of mGluR5 for several actions of alcohol and support the hypothesis that some effects of acamprosate require mGluR5 signalling. "

 

And most surprisingly, in this study, Acamprosate did not compete at all with NMDA for glutamate binding sites while fully competing with trans-ACPD (a selective mGluR agonist) for glutamate sites:

 

Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors

https://pubmed.ncbi.nlm.nih.gov/12500101/

"Results: Na-acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na-acamprosate displayed total competition with trans-ACPD."

"In turn, Na-acamprosate and SIB-1893 had no direct effects on NMDA-induced neurotoxicity."

"Conclusions: Na-acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-acamprosate and SIB-1893 support an interaction of Na-acamprosate at mGluR5s. The neuroprotective properties of acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs."

 

Maybe I'm misinterpreting this study, but doesn't that suggest that Acamprosate actually works on mGluR receptors, NOT on NMDA receptors as previously believed?

 

If you view the Wikipedia page for Acamprosate (https://en.wikipedia.org/wiki/Acamprosate#Pharmacology) the NMDA receptor (one of the major types of ionotropic glutamate receptors) is the only glutamate receptor mentioned. There is zero mention of metabotropic ones.

 

And if you view the Wikipedia pages for the two main mGluR receptors (https://en.wikipedia.org/wiki/Metabotropic_glutamate_receptor_5#Ligands & https://en.wikipedia.org/wiki/Metabotropic_glutamate_receptor_1#Ligands) Acamprosate is not listed anywhere as a ligand. All of the ligands listed are either experimental drugs used for research purposes only, or are not yet approved for medical use.

 

Yet Acamprosate does exhibit action at mGluRs

 

So my main question is this:

 

Does anyone know of any other approved medications, like Acamprosate, that work (at least partially) on Metabotropic Glutamate receptors? Specifically ones that antagonize or negatively modulate mGluR1 and/or mGluR5?

 

Thank you for any assistance!

 

 

Edited by Furniture, 17 November 2023 - 07:10 PM.

[Galaxyshock]

Good that there's more interest in metabotropic glutamate receptors, very interesting area for drug/nootropic development. 

 

I remember reading that Lithium antagonizes mGluR1 and mGluR5 but haven't looked that much into it. Lithium of course affects a bunch of other neurotransmitters too so probably not ideal medication for that purpose.

[Galaxyshock]

I wonder what happens if mGluRs are strongly antagonized though? Is there some kind of dissociative effect similar to antagonizing ionotropic glutamate receptors (NMDA, AMPA, Kainate), or something very different?

 

I have thought that metabotropic glutamate receptors activation acts as "observer" of human consciousness. We know that blocking ionotropic glutamate receptors with dissociatives like Ketamine or the endogenous Kynurenic acid results in detachment from reality and hallucinosis, but they are still observed by the person as mGluRs aren't touched. NMDA activation to me seems to be something that attaches the consciousness to reality. Just something I have thought about, I could very well be wrong here hehe. 

[Furniture]

I wonder what happens if mGluRs are strongly antagonized though? Is there some kind of dissociative effect similar to antagonizing ionotropic glutamate receptors (NMDA, AMPA, Kainate), or something very different?

 

I have thought that metabotropic glutamate receptors activation acts as "observer" of human consciousness. We know that blocking ionotropic glutamate receptors with dissociatives like Ketamine or the endogenous Kynurenic acid results in detachment from reality and hallucinosis, but they are still observed by the person as mGluRs aren't touched. NMDA activation to me seems to be something that attaches the consciousness to reality. Just something I have thought about, I could very well be wrong here hehe. 

 

I'm really not sure about any of that. I have read, though, that antagonizing mGluR5 and/or mGluR1 can produce one of the most powerful & immediate anxiolytic responses of any receptor target, stronger than that of Benzodiazepines' effects on GABA-A. 

 

Where did you get the idea that "metabotropic glutamate receptors activation acts as "observer" of human consciousness". That's an interesting concept. Is there research behind that? Or did you just glean this from personal experience somehow?

[Galaxyshock]

I'm really not sure about any of that. I have read, though, that antagonizing mGluR5 and/or mGluR1 can produce one of the most powerful & immediate anxiolytic responses of any receptor target, stronger than that of Benzodiazepines' effects on GABA-A. 

 

Where did you get the idea that "metabotropic glutamate receptors activation acts as "observer" of human consciousness". That's an interesting concept. Is there research behind that? Or did you just glean this from personal experience somehow?

 

Yeah I've heard that anxiolytic effect can be powerful, but I do wonder are there side effects to it? Glutamate is the major excitatory neurotransmitter so blocking its action on a receptor surely can produce interesting effects but perhaps also negative action on cognition or something. As somebody who has general anxiety disorder I would definitely be interested trying a specific mGluR5 and/or mGluR1 antagonist though.

 

It's just a wild idea based on my own experience with things that affect mGluRs like Fasoracetam, NAC, Suma root etc. To me it seems activation of mGluRs increases this "observing and witnessing" of reality whereas blocking those receptors sort of decreases it. Again it's just some idea I have in mind, I haven't looked much into research of mGluRs and cognition/brain health, should perhaps do that. It's nice to speculate though, perhaps one day we better understand the connection of different neurotransmitters (and their receptors) and the human consciousness.