Writeup | mGluR5 PAMs and Neurological Relevance
mGluR5 potentiation with a PAM may be the most nootropic pathway currently known.
mGluR5 pairs with (and works directly with) mGluR3 and Muscarinic M1 to be one of the most significant contributors to working memory and cognition. This post will look into the relevance of the receptor, and how we can modulate it to potentially increase cognition.
Introduction to mGluR5
Metabotropic glutamate receptor 5 (aka mGlu5, GRM5) is a part of the larger family of 1-8 metabotropic glutamate receptors which have different functions [1]. Through personal research, mGluR3 & mGluR5 are the most attractive to positively modulate, as there are a lot of studies proving their efficacy when approached correctly.
Like mGluR3, mGluR5 was classically defined as having a generally presynaptic location in neuronal circuits, however in higher cortical circuits in primates, it is localised post-synaptically/perisynapticially [2][3], where it strengthens synaptic activity rather than decreasing it.
mGluR5 is implicated in many different neurological functions and conditions, including signaling in adaptive learning [11], working memory [9][10], addiction [12][14], protection against stress-induced dysfunction, and many other neurological conditions (continued later).
In fear conditioning tests, mGluR5 knockout mice showed impaired acquisition of conditioned fear compared to wildtype mice. More strikingly, they showed a complete deficit in extinction of both context and auditory conditioned fear. [31]
The study provides evidence that mGluR5 is critical for inhibitory learning mechanisms involved in suppressing previous learned associations and adapting behavior to new situations. This proves that mGluR5 does not just have an impact in terms of working memory, but also a direct modulatory effect on learning.
There is a lot of research on negative mGluR5 modulators, as they initially seem like a good option. However, mGluR5 has a dual response for both NAMs and PAMs, with both NAMs and PAMs showing anti-addictive properties in some studies [12][14]. This could be to do with an inverse response at low doses, or through some other factor.
One interesting fact is that Fluoride and Arsenic decrease mGluR5 protein expression [13], showing another point of neurotoxicity and reason for their damaging potential.
Relationship with mGluR3 and M1
mGluR3-induced postsynaptic LTD is dependant on mGluR5 [26] - activation of mGluR3 induces LTD of excitatory transmission that requires co-activation of mGluR5, and an mGluR5 negative allosteric modulator blocks mGluR3-LTD. This induced LTD is vital in preventing amygdalo-cortical dysfunction [27], and potentating mGluR5 using a PAM rescues the impairment in mGluR3/mGluR5-LTD caused by acute stress exposure [26].
In addition to mGluR3-LTD, mGluR5 is also required for muscarinic M1-induced LTD [28]. This is very notable as M1 enhancement enhances cognition [29], showing how mGluR3-mGluR5-M1 work in tandem.
Using a PAM for improved efficacy
mGluR5 being part of metabotropic group II (mGluR1/5) has typically been associated with increased NMDA receptor activity and risk of excitotoxicity [5]. This was previously a concern for increasing mGluR5 activity, because when using agonists/ago-allosterics, the increased mGluR5 could cause excitotoxicity/NMDA over-activation, which is not desirable. mGluR5 agonism also causes reinforcement of addictive behaviors [6] which is also undesirable.
Then how can mGluR5 be modulated to mitigate these issues? That is where the relevance of a PAM (Positive Allosteric Modulator) comes in. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning [8].
mGluR5 has at least two distinct allosteric binding sites [4], and has many methods of modulation. The most notable modulator of mGluR5 is VU0409551 due to its preference for mGlu5-Gαq rather than mGlu5-NMDA, and optimal pharmacokinetic profile.
In studies, VU0409551 did not induce neurotoxicity or seizures with chronic high doses, unlike other mGluR5 PAMs/agonists [9]. VU0409551 has biased activity towards mGluR5-mediated Gαq signaling pathways and not mGluR5-NMDAR modulation [9][26].
In vivo, VU0409551 showed robust wake-promoting effects and improved performance in rodent models of antipsychotic-like activity (reversal of MK-801 hyperlocomotion) and cognition (fear conditioning, novel object recognition, delayed non-matching to position). [9][10]
VU0409551 also enhances branched dendritic spines significantly, doubling their distribution in the hippocampus of treated mice after 8 days of treatment [30]. This leads to greater synaptic maturation; this is because the branched type of spines is the last stage of maturation of dendritic spines.
Fig 5f - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317718/
Pharmacokinetic Profile of VU0409551
VU0409551 (also called JNJ-46778212) emerged as a lead candidate from a medicinal chemistry program optimizing compounds based on HTS hits. It has an oxazolo[5,4-c]pyridine core structure. [32]
In in vitro assays, VU0409551 potentiated mGlu5 response with an EC50 of 260 nM and 84% efficacy. It selectively modulated mGlu5 over other mGlu receptors.
It has good oral bioavailability (>40%), a decent half life (3-7 hours est.), a relatively low dose at predicted 10mg IN / 25mg Oral dose in humans.
Potential downsides of this compound could be a high priced synthesis due to its relatively large structure, and also it does not have the best predictions in safety software. However, as a compound it has shown some of the highest efficacy in animal trials for cognitive enhancement to date, and it should be looked into more.
Secondary Effects of mGluR5 Positive Allosterics
- Treating Alzheimer's - In rodent models [29], potentiating mGluR5 (especially with PAMs) reduces cognitive deficits in Alz models. Lowered mGluR5 has also been found to be an early sign at the start of Alzheimer's disease [33].
- Treating Huntington's Disease - In one study, mGluR5 rescued deficits in H.D, ameriolating deficits in branched dentric spines and spine maturation [30]. In another study [31], and mGluR5 PAM showed a high level of neuroprotection and efficacy for treating huntington's disease.
- Treating Addiction - In rodent models using cocaine and methamphetamine, positive allosteric modulation of mGluR5 had beneficial effects on extinction learning, and reduced drug seeking. [12][14][22]
- Treating Schizophrenia - Low mGluR5 receptor availability has been associated with increased severity of schizophrenic symptoms, and increasing mGluR5 may be a novel approach for treating the disorder [7]. mGluR5 PAMs produce significant efficacy in at least two animal models that predict efficacy in treatment of positive symptoms of schizophrenia [21].
- Treating Stress/PTSD - mGluR5 has an essential role in promoting stress resilience [16] through ΔFosB and mGluR3-LTD [26], and increasing it may be a novel approach for being resilient to stress [17][18][19]. Due to mGluR5 being reactive to stress to induce resilience, it could easily be misidentified as a positive modulator of stress based just off of association [20], so this must be thought on before conclusions are made.
- Treating Autism (?) - In autism, mGluR5 expression in the dlPFC is decreased [23], however there are inconsistencies with studies depending on brain regions [24][25].
Discussion
mGluR5 seems to be very relevant for high-level cognition, and also relevant for a wide range of neurological disorders.
Using PAMs that focus on Gαq rather than NMDA seem to be superior to agonists or NAMs and should definitely be investigated further. Some of the results shown within these studies have blown me away, and potentiating mGluR5 alongside mGluR3 likely seems like a really good approach for increasing high-level cognition.
Enhancing mGluR3 at the same time as mGluR5 would also have a potent anti-addictive effect as seen in studies using GCP-II inhibitors and VU0409551. Rather than targeting dopamine directly or targeting dopamine subunits, targeting mGluRs and dlPFC-specific receptors looks to be a better (and more effective approach). Addiction causes dysfunction in the dlPFC and by enhancing it's activity (and delay cell firing) it increases self-control by lowering the power of the amygdala.
This has been shown in studies on guanfacine and gcp-ii inhibitors before, however guanfacine has the limitation of sedation that gives it a roof on it's efficacy. Compounds that do not modulate HCN channels do not have this downside, so it lets them have a much higher ceiling for cognitive enhancement, and Guanfacine is but a taste of what dlpfc enhancement can be.
Thank you for reading.
You can check out our post on mGluR3 enhancement here: Link
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