Glutamatergics

Glutamate is an amino acid that acts as an excitatory neurotransmitter, and this serves as a glutamate definition. Glutamate receptors are triggered when glutamate binds to the glutamate receptor subunits. NMDA receptors are common targets for glutamatergics, causing changes in the NMDA channel to either increase or decrease neuron synapse transmission.¹

Glutamate and acetylcholine are often referred to as learning neurotransmitters and their function is relevant to studies of neurochemistry, memory, and cognitive enhancement. AMPA agonists are used primarily in research for long-term potentiation and prevention of cognitive decline,² while NMDA antagonists are used as dissociative anaesthetics and investigational antidepressants and neuroprotective agents.³

Glutamate neurotransmitter functions

Glutamatergics are substances that target the glutamate receptors. Glutamate receptor proteins respond to glutamate binding and glutamate ligands – glutamate being the most abundant neurotransmitter in the human brain and central nervous system.

Glutamate is the primary stimulating neurotransmitter and also is the precursor for GABA. Glutamate receptors are especially involved in glutamate-mediated signal transduction. Glutamate is an especially intracellular compound. It is found predominantly within nerve terminals and synaptic vesicles. The concentration of glutamate in the extracellular fluid in extremely low compared to its intracellular concentration.

In fact, it is said that around 99.99% of glutamate is found inside cells. The remarkable feat of maintaining such a low extracellular concentration of glutamate is a result of the intricate glutamate uptake mechanisms.⁴ Glutamate uptake receptors trigger the action of glutamate transporter proteins, which work by binding to extracellular glutamate and ‘forcing’ it inside cells that already have a very high glutamate concentration.

Cells respond to extracellular glutamate through the membrane-bound glutamate receptor proteins. Glutamate is an excitatory neurotransmitter and it triggers the action of three major glutamate receptors. The primary glutamate function is to trigger the action of the follow three receptors, which mediate excitatory synaptic transmission:

1. NMDA
2. AMPA/K
3. mGluR

Glutamatergic substances have either a specific or broad-based action on one or more of the three glutamate receptors. They can act as either agonists or antagonists or on nearby proteins to influence receptor function. The mechanisms of action of various glutamate substances differ greatly.

NMDA receptor and AMPA/mGluR receptor function

NMDA receptors and AMPA receptors are the primary ionotropic receptor proteins in the nerve cells (along with Kainate). The receptors respond to glutamate and glutamatergic substances to promote signal transduction. Both AMPA and NMDA receptors are excitatory ionotropic – increasing electrochemical signal transduction through synapses.⁵

On the one hand, AMPA receptors primarily mediate fast excitatory transmission through a nonselective cation channel and a desensitization mechanism. On the other hand, NMDA receptors use a similar nonselective cation channel which only opens when the NMDA receptor is bound to glutamate.⁶

The NMDA receptor has an ability to produce long-term changes in ion activity and neuron pathway structures, known as long-term potentiation (LTP). ⁷ LTP is of great interest in modern neuroscience research, particularly in the fields of cognitive enhancement, neuroprotection, and neuroplasticity.

The mGluR receptors have 8 subtypes and are primarily involved in regulating the activity of AMPA and NMDA receptors. mGluR receptors are of particular interest to scientists and researchers involved in the research of neurological disorders like Alzheimer’s disease, Parkinson’s disease, anxiety, depression, and schizophrenia.

mGluR receptors are G-protein-coupled receptors and their conformation changes in response to glutamate binding, triggering a cascade of modulating effects – either inhibitory or excitatory – on the AMPA and NMDA receptors.⁸

Racetams

Racetams are a class of chemical substances that all contain a pyrrolidone nucleus. Racetams are drugs that were developed primary for research into cognitive enhancement and memory function. All racetams have different methods of action, but tend to function by modulating glutamatergic receptors like AMPA, mGluR and NMDA receptors.

Glutamatergics on Newmind

D-cycloserine is a broad-spectrum antibiotic with glycinergic activity. D-cycloserine was first sold and marketed as an antibiotic drug. It is still used in combination with 5 other drugs for the treatment of Mycobacterium avium complex and tuberculosis.

New research has since demonstrated D-cycloserine’s potent activity on NMDA receptors – acting as a partial agonist at the Glycine binding site. This activity is thought to have a potential for therapeutic use with analgesic applications. ⁹ Recent D-cycloserine reviews have indicated that it may have potential for use in cognitive enhancement research.¹⁰

Oxiracetam is one of the first-tier racetam compounds, being produced just after Piracetam and Aniracetam. It is a racetam compound and is involved in cognitive and neuroscience research for memory and as a potential dementia therapeutic.

A number of studies have shown that Oxiracetam may have a function in reducing cognitive decline, especially organic, age-related, cognitive decline. ¹¹ Oxiracetam may have the potential to increase long-term potentiation and it is a positive modulator of AMPA receptors.¹²

Sunifiram, or DM-235, is a racetam-like molecule (piperazine alkaloid) with similar functions to those of oxiracetam. It holds potential for cognitive enhancement research but is still understudied at this time. It has anti amnesiac properties that are stronger than those of Piracetam.¹³

Pharmacological studies have suggested that Sunifram enhances NMDA-dependant signaling and acts as a ligand at the glycine-binding site. It has also been confirmed to activate CAMKII and PCK-alpha receptors and to increase long-term potentiation through its effects on NMDA-receptors.¹⁴

Pramiracetam, like other racetams, was developed with the intention of creating a drug to enhance memory formation and long-term potentiation. Its initial synthesis was from the original racetam, Piracetam.

Limited studies have indicated a strong potential for use in memory enhancement and as a potential therapeutic for cognitive decline. ¹⁵ It appears to modulate EEG activity in both humans and animals and may have an ability to enhance choline-uptake.¹⁶

Unifiram, or DM-232, is a powerful AMPAKine-like Nootropic molecule with the ability to increase long-term potentiation and cognition at a magnitude of up to three times that of Piracetam.¹⁷

Phenylpiracetam is the earliest derivative of Piracetam – the only modification was an addition of a phenyl group. The addition of the phenyl group appears to enhance its uptake into cells and its efficacy. Phenylpiracetam has been used in research for cognitive enhancement, as an antidepressant, for stimulatory effects, and as an anti-inflammatory.¹⁸ The majority of this research was conducted in Russia and is not available in English-language scientific/medical journals.

Noopept (GVS-111) – N-phenylacetyl-L-prolylglycine ethyl ester – is a Nootropic substance with similar effects to Piracetam. It is grouped with other racetam compounds but is technically not a racetam due to its lack of a 2-oxo-pyrollidine skeleton. Noopept is considered to be a breakthrough substance in neuroscience research for cognitive decline and is often said to be roughly 1000 times more potent than Piracetam.¹⁹

Noopept affects alpha brainwave activity and is thought to function as a NMDA receptor agonist, as well as a showing competitive binding at AMPA binding sites. Noopept has shown remarkable anti-inflammatory activity along with cognitive enhancement and increased memory function in animal studies.²⁰

Glutamatergic Applications

The application of glutamatergic drugs depends on their respective mechanisms of action. For example, NMDA antagonists are used as sedatives and tranquilizers while NMDA agonists are used for cognitive enhancement research.

Antagonists of NMDA receptors include a number of controlled substances including Ketamine, dextromethorphan (DXM), phencyclidine (PCP), and nitrous oxide – all classified as dissociative drugs. Applications of these substances include emergency room treatment for burn victims (ketamine), and cough suppressants (DXM metabolites).

Increased levels of endogenous NMDA antagonists may be linked to psychological and neurological disorders like schizophrenia. NMDA antagonists are thought to act as neurotoxins at high doses, causing cognitive deficits and cell death.

NMDA agonists, as discussed above, are used primarily for research into memory and cognition enhancement, with a potential to improve long-term potentiation and learning. These substances have an opposite effect to NMDA antagonists and may also help promote neuroprotection – in contrast to NMDA antagonists.

Human and Animal Toxicity

The Glutamatergics all have different mechanisms of action and therefore have different toxicity levels. Please check out the research for each product to learn more about toxicity ratings. Please note that chemicals sold on Newmind are specifically for research purposes and are strictly not for human consumption or veterinary use.

To access our full range of products, you will first need to submit an account approval application specifying the type of research you are conducting and the facilities at your disposal.

¹ “Neuroscience. 2nd edition: Glutamate Receptors”, Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001

² “NMDA Receptors” University of Bristol, Centre for Synaptic Plasticity, available online, retrieved on March 21, 2017

³ “NMDA receptors as targets for treatment of depression”, by Dr Arturas Volianskis, ABCam Neuroscience, available online, retrieved on March 21, 2017

⁴ “Glutamate as a Neurotransmitter - An overview”, by Niels Chr. Danbolt, Danbolt, 2001: Prog. Neurobiol. 65, 1-105.

⁵ “Glutamatergic receptors: AMPA, NMDA and mGluR”, by Dr. Janet Fitzakerley, 2014 University of Minnesota Medical School Duluth, available online, retrieved on March 21, 2017

⁶ ML. Blanke, AMJ Van Dongen , “Biology of the NMDA Receptor, Chapter 13: Activation Mechanisms of the NMDA Receptor”, Van Dongen AM, editor. Boca Raton (FL): CRC Press/Taylor & Francis; 2009.

⁷ C Lüscher, RC Malenka, “NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD)”, Published in Advance April 17, 2012, doi: 10.1101

⁸ CM. Niswender, PJ Conn, “Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease”, Annu Rev Pharmacol Toxicol. 2010; 50: 295–322, doi: 10.1146/annurev.pharmtox.011008.145533

⁹ “D-Cyloserine: Compound Summary for CID 6234”, PubChem, Online Chemistry Database, available online, retrieved on March 21, 2017

¹⁰ SG Hofmann, “D-cycloserine for Treating Anxiety Disorders: Making Good Exposures Better and Bad Exposures Worse”, Depress Anxiety. 2014 Mar; 31(3): 175–177.doi: 10.1002/da.22257

¹¹ TM Itil et al., “The effects of oxiracetam (ISF 2522) in patients with organic brain syndrome (a double-blind controlled study with piracetam)”, Drug Dev. Research, Volume 2, Issue 5, 1982, Pages 447–461

¹² M Marchi et al., “Oxiracetam increases the release of endogenous glutamate from depolarized rat hippocampal slices”, Eur J Pharmacol. 1990 Aug 28;185(2-3):247-9.

¹³ E Martinin et al., “Design, synthesis and preliminary pharmacological evaluation of new piperidine and piperazine derivatives as cognition-enhancers”, Bioorg Med Chem. 2008 Feb 1;16(3):1431-43.

¹⁴ S Moriguchi et al., “Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of N-methyl-D-aspartate receptor”, Hippocampus. 2013 Oct;23(10):942-51. doi: 10.1002/hipo.22150

¹⁵ McLean A Jr et al., “Placebo-controlled study of pramiracetam in young males with memory and cognitive problems resulting from head injury and anoxia”, Brain Inj. 1991 Oct-Dec;5(4):375-80.

¹⁶ De Vreese LP et al., “Memory training and drug therapy act differently on memory and metamemory functioning: evidence from a pilot study”, Arch Gerontol Geriatr. 1996;22 Suppl 1:9-22

¹⁷ C Ghelardini et al., “The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats”, Drug Dev. Research, Volume 56, Issue 1, May 2002, Pages 23–32, DOI: 10.1002/ddr.10055

¹⁸ Malykh AG, Sadaie MR, “Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders”, Drugs. 2010 Feb 12;70(3):287-312.

¹⁹ RU Ostrovskaia et al., “[The original novel nootropic and neuroprotective agent noopept]”, Eksp Klin Farmakol. 2002 Sep-Oct;65(5):66-72.

²⁰ RU Ostrovskaya et al., “Memory restoring and neuroprotective effects of the proline-containing dipeptide, GVS-111, in a photochemical stroke model”, Behav Pharmacol. 1999 Sep;10(5):549-53.