Quisqualic acid

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Quisqualic acid
Quisqualic acid.svg
Quisqualic acid spacefill.png
Quisqualic acid.png
Names
IUPAC name
3-(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)-L-alanine
Systematic IUPAC name
(2S)-2-Amino-3-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)propanoic acid
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.164.809 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH Quisqualic+Acid
PubChem CID
UNII
  • InChI=1S/C5H7N3O5/c6-2(3(9)10)1-8-4(11)7-5(12)13-8/h2H,1,6H2,(H,9,10)(H,7,11,12)/t2-/m0/s1 Yes check.svgY
    Key: ASNFTDCKZKHJSW-REOHCLBHSA-N Yes check.svgY
  • InChI=1/C5H7N3O5/c6-2(3(9)10)1-8-4(11)7-5(12)13-8/h2H,1,6H2,(H,9,10)(H,7,11,12)/t2-/m0/s1
    Key: ASNFTDCKZKHJSW-REOHCLBHBE
  • O=C1NC(=O)ON1C[C@H](N)C(=O)O
Properties
C5H7N3O5
Molar mass 189.126 g/mol
Melting point 187 to 188 °C (369 to 370 °F; 460 to 461 K) decomposes
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Quisqualic acid is an agonist of the AMPA, kainate, and group I metabotropic glutamate receptors. It is one of the most potent AMPA receptor agonists known. [1] [2] [3] [4] It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord. [5] [6] [7] Quisqualic acid occurs naturally in the seeds of Quisqualis species.

Contents

Research conducted by the USDA Agricultural Research Service, has demonstrated quisqualic acid is also present within the flower petals of zonal geranium ( Pelargonium x hortorum) and is responsible for causing rigid paralysis of the Japanese beetle. [8] [9] Quisqualic acid is thought to mimic L-glutamic acid, which is a neurotransmitter in the insect neuromuscular junction and mammalian central nervous system. [10]

History

Combretum indicum ( Quisqualis indica var. villosa) is native to tropical Asia but is still doubt whether is indigenous from Africa or was introduced there. Since the amino acid that can be isolated from its fruits can nowadays be made in the lab, the plant is mostly cultivated as an ornamental plant.  

Its fruits are known for having anthelmintic effect, therefore they are used to treat ascariasis. The dried seeds are used to reduce vomiting and to stop diarrhoea, but an oil extracted from the seeds can have purgative properties. The roots are taken as a vermifuge and leaf juice, softened in oil, are applied to treat ulcers, parasitic skin infections or fever.  

The plant is used for pain relief, and in the Indian Ocean islands, a decoction of the leaves is used to bath children with eczema. In the Philippines, people chew the fruits to get rid of the cough and the crushed fruits and seeds are applied to ameliorate nephritis. In Vietnam, they use the root of the plant to treat rheumatism. In Papua New Guinea the plants are taken as a contraceptive medicine.  

However the plant does not have just medicinal use. In west Africa, the long and elastic stems are used for fish weir, fish traps and basketry. The flowers are edible, and they are added in salads to add color.  

The seed oil contains palmitic, oleic, stearic, linoleic, myristic and arachidonic acid. The flowers are rich in the flavonoid glycosides pelargonidin – 3 – glucoside and rutin. The leaves and stem bark are rich in tannins, while from the leafy stem several diphenylpropanoids were isolated.  

The active compound (quisqualic acid) resembles the action of the anthelmintic α-santonin, so in some countries the seeds of the plants are used to substitute for the drug. However, the acid has shown excitatory effects on cultured neurons, as well as in a variety of animal models, as it causes several types of limbic seizures and neuronal necrosis. [11]

The quisqualic acid can be now commercially synthesized, and it functions as an antagonist for its receptor, found in the mammalian central nervous system. [11]

Chemistry

Structure

It is an organic compound, associated with the class of L – alpha – amino acids. These compounds have the L configuration of the alpha carbon atom.  

Quisqualic acid contains, in its structure a five membered, planar, conjugated, aromatic heterocyclic system, consisting of one oxygen atom and two nitrogen atoms at position 2 and 4 of the oxadiazole ring.   The 1,2,4–oxadiazole ring structure is present in many natural products of pharmacological importance. Quisqualic acid, which is extracted from the seeds of Quisqualis indica is a strong antagonist of the α–amino–3–hydroxy–5–methyl–4–isoxazolepropionic acid receptors. [12]

Reactivity and synthesis

Biosynthesis

L – quisqualic acid is a glutamate receptor agonist, acting at AMPA receptors and metabotropic glutamate receptors positively linked to phosphoinositide hydrolysis. It sensitizes neurons in hippocampus to depolarization by L-AP6. [13]

Being a 3, 5 disubstituted oxadiazole, quisqualic acid is a stable compound. [14]

One way of synthesizing quisqualic acid is by enzymatic synthesis. Therefore, cysteine synthase is purified from the leaves of Quisqualis indica var. villosa, showing two forms of this enzyme. Both isolated isoenzymes catalyse the formation of cysteine from O-acetyl-L-serine and hydrogen sulphide, but only one of them catalyses the formation of L – quisqualic acid. [15]

Industrial synthesis

Another way of synthesizing the product is by having L-serine as starting material.  

Initial step in synthesis is the conversion of L-serine to its N-t-butoxycarbonyl derivative. Amine group of serine has to be protected, so di-tert-butyldicarbonate in isopropanol and aqueous sodium hydroxide was added, at room temperature. The result of the reaction is the N-t-Boc protected acid. Acylation of this acid with O-benzylhydroxylamine hydrochloride followed. T-Boc protected serine was treated with one equivalent of isobutyl chloroformate and N-methylmorpholine in dry THF, resulting in mixed anhydride. This than reacts with O – benzylhydroxylamine to give the hydroxamate. The hydroxamate proceeds to be converted into β – lactam, which was hydrolyzed to the hydroxylamino acid (77) by treatment with one equivalent of sodium hydroxide. After acidification with saturated aqueous solution of citric acid, the final product, L-quisqualic acid, was isolated. [16]

Functions

Molecular mechanisms of action

Quisqualic acid is functionally similar to glutamate, which is an endogenous agonist of glutamate's receptors. It functions as a neurotransmitter in insect neuromuscular junction and CNS.  It passes the blood brain barrier and binds to cell surface receptors AMPA and Kainate receptors in the brain. 

AMPA receptor is a type of ionotropic glutamate receptor coupled to ion channels and when bound to a ligand, it modulates the excitability by gating the flow of calcium and sodium ions into the intracellular domain. [17]  On the other hand, kainate receptors are less understood than AMPA receptors. Although, the function is somewhat similar: the ion channel permeates the flow of sodium and potassium ions, and to a lower extent the Calcium ions.[ citation needed ]

As mentioned, binding of quisqualic acid to these receptors leads to an influx of calcium and sodium ions into the neurons, which triggers downstream signaling cascades. Calcium signaling involves protein effectors such as kinases (CaMK, MAPK/ERKs), CREB-transcription factor and various phosphatases. It regulates gene expression and may modify the properties of the receptors. [18]

 Sodium and calcium ions together generate an excitatory postsynaptic potential (EPSP) that triggers action potentials. It's worthwhile to mention that overactivation of glutamate receptors and kainate receptors lead to excitotoxicity and neurological damage. [18]

A greater dose of quisqualic acid over activates these receptors that can induce seizures, due to prolonged action potentials firing the neurons. Quisqualic acid is also associated with various neurological disorders such as epilepsy and stroke. [19]

Metabotropic glutamate receptors, also known as mGluRs are a type of glutamate receptor which are members of the G-protein coupled receptors. These receptors are important in neural communication, memory formation, learning and regulation. Like Glutamate, quisqualic acid binds to this receptor and shows even a higher potency, mainly for mGlu1 and mGlu5 and exert its effects through a complex second messenger system. [20] Activation of these receptors leads to an increase in inositol triphosphate (IP3) and diacylglycerol (DAG) by the activation of phospholipase C (PLC). Eventually, IP3 diffuses to bind to IP3 receptors on the ER, which are calcium channels that eventually increase the Calcium concentration in the cell. [21]

Modulation of NMDA receptor

The effects of quisqualic acid depend on the location and context. These 2 receptors are known to potentiate the activity of N-methyl-D-aspartate receptors (NMDARs), a certain type of ion channel that is a neurotoxic. Excessive amounts of NMDA have been found to cause harm to the neurons in the presence of mGlu1 and mGlu5 receptors. [22]

Effects on plasticity

Activation of group 1 mGluRs are implicated in synaptic plasticity and contribute to both neurotoxicity and neuroprotection such as protection of the retina against NMDA toxicity, mentioned above. [23] It causes a reduction in ZENK expression, which leads to myopia in chicken. [24]

Role in disease 

Studies on mice have suggested that mGlu1 may be involved in the development of certain cancers. [25] Knowing that these types of receptors are mostly localized in the thalamus, hypothalamus and caudate nucleus regions of the brain, the overactivation of these receptors by quisqualic acid can suggest a potential role in movement disorders. 

FamilyTypeMechanism
AMPAionotropicIncrease membrane permeability for sodium, calcium, and potassium
KainateionotropicIncrease membrane permeability for sodium and potassium
NMDAionotropicIncrease membrane permeability for calcium
Metabotropic Group 1G-coupled proteinsActivation of phospholipase C: increase of IP3 and DAG

Use/purpose, availability, efficacy, side effects/ adverse effects

Quisqualic acid is an excitatory amino acid (EAA) and a potent agonist of metabotropic glutamate receptors, where evidence shows that activation of these receptors may cause a long lasting sensitization of neurons to depolarization, a phenomenon called the “Quis effect ”. [26]

The first uses of quisqualic acid in research date back to 1975, [27] where the first description of the acid noted that it had strong excitatory effects in the spinal cords of frogs and rats as well as on the neuromuscular junction in crayfish. [16] Since then, its main use in research has been as template for excitotoxic models of spinal cord injury (SCI) studies. When injected into the spinal cord, quisqualic acid can cause excessive activation of glutamate receptors, leading to neuronal damage and loss. [28] This excitotoxic model has been used to study the mechanisms of SCI and to develop potential treatments for related conditions. Several studies have demonstrated experimentally the similarity between the pathology and symptoms of SCI induced by quisqualic acid injections and those observed in clinical spinal cord injuries. [28] [29]

After administration of quis-injection, spinal neurons located close to areas of neuronal degeneration and cavitation exhibit a decrease in mechanical threshold, meaning they become more sensitive to mechanical stimuli. This heightened sensitivity is accompanied by prolonged after discharge responses. These results suggest that excitatory amino acid agonists can induce morphological changes in the spinal cord, which can lead to physiological changes in adjacent neurons, ultimately resulting in altered mechanosensitivity. [28] [30]

There is evidence to suggest that excitatory amino acids like quisqualic acid play a significant role in the induction of cell death following stroke, hypoxia-ischemia, and traumatic brain injury . [28] [31] [32]

Studies involving the binding of quisqualic acid have indicated that the amino acid does not show selectivity for a singular specific receptor subtype, which was initially identified as the quisqualate receptor. [27] Instead, it demonstrates high affinity for other types of excitatory amino acid receptors, including kainate, AMPA, and metabotropic receptors, as well as some transport sites, such as the chloride-dependent L-AP4-sensitive sites. In addition, it also exhibits affinity for certain enzymes responsible for cleaving dipeptides, including the enzyme responsible for cleaving N-acetyl-aspartylglutamate (NAALADase) . [27] [33]

Regarding bioavailability, no database information is present, as there is limited research on its pharmacokinetics. However, even though the bioavailability is not well established, studies in rats suggest that age may play a role in the presence of administered quisqualic acid effects. An experiment which was done on rats within two age groups (20-days-old and 60-days-old) showed that, when given quisqualic acid microinjections, 60-day-old rats had more seizures compared to the younger rats. Additionally, the rats were given the same amount of quisqualic acid, however the immature animals received a higher dosage per body weight, implying that the harm inflicted by the excitatory amino acid may have been comparatively lower in the younger animals. [34]

Quisqualic acid has not been used in clinical trials and currently has no medicinal use, [35] therefore no information about adverse or side effects has been reported. 

There has been a significant decrease in research done on quisqualic acid after the early 2000s, possibly attributed to a lack of specificity and/or lack of other clinical uses apart from SCI investigations, which have progressed with other methods of research. [35]

Metabolism/Biotransformation

Quisqualic acid enters the body through different routes, such as ingestion, inhalation, or injection. The ADME (absorption, distribution, metabolism and excretion) process has been studied by means of various animal models in the laboratory. 

Absorption: quisqualic acid is a small and lipophilic molecule, thus is expected to be rapid. It is predicted to be absorbed in the human intestine and from then it circulates to the blood brain barrier. [34] Analysis of amino acid transport systems is complex by the presence of multiple transporters with overlapping specificity. Since glutamate and quisqualic acid are similar, it is predicted that sodium/potassium transport in the gastrointestinal tract is the absorption site of the acid. 

Distribution: knowing the receptors it binds to, it can be readily predicted where the acid is present such as: hippocampus, basal ganglia, olfactory regions. 

Metabolism: quisqualic acid is thought to be metabolized in the liver by oxidative metabolism carried out by cytochrome P450 enzymes, Glutathione S-transferase (detoxifying agents). A study showed that the exposure to quisqualic acid revealed that P450, GST were involved. [36] It is also confirmed by using admetSAR tool to evaluate chemical ADMET properties. [34] Its metabolites are thought to be NMDA and quinolinic acid. 

Excretion: Mostly, as a rule of thumb, amino acids undergo transamination/deamination in the liver. Thus amino acids are converted into ammonia and keto acids, which are eventually excreted via the kidneys. 

It is worth mentioning that the pharmacokinetics of quisqualic acid has not been extensively studied and there is sparse information available on its ADME process. Therefore, more research is needed to fully understand the metabolism of the acid in the body. 

See also

Related Research Articles

<i>N</i>-Methyl-<small>D</small>-aspartic acid Amino acid derivative

N-methyl-D-aspartic acid or N-methyl-D-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors. NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.

<span class="mw-page-title-main">AMPA receptor</span> Transmembrane protein family

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel domain to be crystallized.

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. IPSPs were first investigated in motorneurons by David P. C. Lloyd, John Eccles and Rodolfo Llinás in the 1950s and 1960s. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell to cell signalling. Inhibitory presynaptic neurons release neurotransmitters that then bind to the postsynaptic receptors; this induces a change in the permeability of the postsynaptic neuronal membrane to particular ions. An electric current that changes the postsynaptic membrane potential to create a more negative postsynaptic potential is generated, i.e. the postsynaptic membrane potential becomes more negative than the resting membrane potential, and this is called hyperpolarisation. To generate an action potential, the postsynaptic membrane must depolarize—the membrane potential must reach a voltage threshold more positive than the resting membrane potential. Therefore, hyperpolarisation of the postsynaptic membrane makes it less likely for depolarisation to sufficiently occur to generate an action potential in the postsynaptic neurone.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

<span class="mw-page-title-main">Excitotoxicity</span> Process that kills nerve cells

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

<span class="mw-page-title-main">Kainate receptor</span> Class of ionotropic glutamate receptors

Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the algae Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.

<span class="mw-page-title-main">Kainic acid</span> Chemical compound

Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervous system. Glutamate is produced by the cell's metabolic processes and there are four major classifications of glutamate receptors: NMDA receptors, AMPA receptors, kainate receptors, and the metabotropic glutamate receptors. Kainic acid is an agonist for kainate receptors, a type of ionotropic glutamate receptor. Kainate receptors likely control a sodium channel that produces excitatory postsynaptic potentials (EPSPs) when glutamate binds.

<span class="mw-page-title-main">Metabotropic glutamate receptor</span> Type of glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane. The family of glutamate transporters is composed of two primary subclasses: the excitatory amino acid transporter (EAAT) family and vesicular glutamate transporter (VGLUT) family. In the brain, EAATs remove glutamate from the synaptic cleft and extrasynaptic sites via glutamate reuptake into glial cells and neurons, while VGLUTs move glutamate from the cell cytoplasm into synaptic vesicles. Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues, including the heart, liver, testes, and bone. They exhibit stereoselectivity for L-glutamate but transport both L-aspartate and D-aspartate.

<span class="mw-page-title-main">DNQX</span> Chemical compound

DNQX (6,7-dinitroquinoxaline-2,3-dione) is a competitive antagonist at AMPA and kainate receptors, two ionotropic glutamate receptor (iGluR) subfamilies. It is used in a variety of molecular biology subfields, notably neurophysiology, to assist researchers in determining the properties of various types of ion channels and their potential applications in medicine.

<span class="mw-page-title-main">GRIA3</span> Protein-coding gene in humans

Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.

<span class="mw-page-title-main">GRIA2</span> Mammalian protein found in Homo sapiens

Glutamate ionotropic receptor AMPA type subunit 2 is a protein that in humans is encoded by the GRIA2 gene and it is a subunit found in the AMPA receptors.

<span class="mw-page-title-main">GRIK1</span> Protein-coding gene in the species Homo sapiens

Glutamate receptor, ionotropic, kainate 1, also known as GRIK1, is a protein that in humans is encoded by the GRIK1 gene.

<span class="mw-page-title-main">5-Fluorowillardiine</span> Chemical compound

5-Fluorowillardiine is a selective agonist for the AMPA receptor, with only limited effects at the kainate receptor. It is an excitotoxic neurotoxin when used in vivo and so is rarely used in intact animals, but it is widely used to selectively stimulate AMPA receptors in vitro. It is structurally similar to the compound willardiine, which is also an agonist for the AMPA and kainate receptors. Willardiine occurs naturally in Mariosousa willardiana and Acacia sensu lato.

<span class="mw-page-title-main">Quisqualamine</span> Chemical compound

Quisqualamine is the α-decarboxylated analogue of quisqualic acid, as well as a relative of the neurotransmitters glutamate and γ-aminobutyric acid (GABA). α-Decarboxylation of excitatory amino acids can produce derivatives with inhibitory effects. Indeed, unlike quisqualic acid, quisqualamine has central depressant and neuroprotective properties and appears to act predominantly as an agonist of the GABAA receptor and also to a lesser extent as an agonist of the glycine receptor, due to the facts that its actions are inhibited in vitro by GABAA antagonists like bicuculline and picrotoxin and by the glycine antagonist strychnine, respectively. Mg2+ and DL-AP5, NMDA receptor blockers, CNQX, an antagonist of both the AMPA and kainate receptors, and 2-hydroxysaclofen, a GABAB receptor antagonist, do not affect quisqualamine's actions in vitro, suggesting that it does not directly affect the ionotropic glutamate receptors or the GABAB receptor in any way. Whether it binds to and acts upon any of the metabotropic glutamate receptors like its analogue quisqualic acid however is unclear.

<span class="mw-page-title-main">Glutamate (neurotransmitter)</span> Anion of glutamic acid in its role as a neurotransmitter

In neuroscience, glutamate is the anion of glutamic acid in its role as a neurotransmitter. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

<span class="mw-page-title-main">Willardiine</span> Chemical compound

Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See: #Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.

References

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  12. ↑ Ram VJ, Sethi A, Nath M, Pratap R (2017). "Chapter 5 - Five-Membered Heterocycles". The Chemistry of Heterocycles: Nomenclature and Chemistry of Three-to-Five Membered Heterocycles. Netherlands: Elsevier. ISBN   978-0-08-101033-4.
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