Chemistry: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
EC Number
  • 637-070-2
KEGG
MeSH Quisqualic+Acid
UNII
Properties
C5H7N3O5
Molar mass 189.126 g/mol
Melting point 187 to 188 °C (369 to 370 °F; 460 to 461 K) decomposes
Hazards
GHS pictograms GHS07: Harmful
GHS Signal word Warning
H302, H312, H332
P261, P264, P270, P271, P280, P301+317Script error: No such module "Preview warning".Category:GHS errors, P302+352, P304+340, P317Script error: No such module "Preview warning".Category:GHS errors, P321, P330, P362+364Script error: No such module "Preview warning".Category:GHS errors, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is ☑Y☒N ?)
Infobox references

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.[2][3][4][5] It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord.[6][7][8] Quisqualic acid occurs naturally in the seeds of Quisqualis species.

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.[9][10] Quisqualic acid is thought to mimic L-glutamic acid, which is a neurotransmitter in the insect neuromuscular junction and mammalian central nervous system.[11]

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.[12]

The quisqualic acid can be now commercially synthesized, and it functions as an antagonist for its receptor, found in the mammalian central nervous system.[12]

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.[13]

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.[14]

Being a 3, 5 disubstituted oxadiazole, quisqualic acid is a stable compound.[15]

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.[16]

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.[17]

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.[18] 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.[19]

 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.[19]

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.[20]

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.[21] 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.[22]

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.[23]

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.[24] It causes a reduction in ZENK expression, which leads to myopia in chicken.[25]

Role in disease 

Studies on mice have suggested that mGlu1 may be involved in the development of certain cancers.[26] 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. 

Family Type Mechanism
AMPA ionotropic Increase membrane permeability for sodium, calcium, and potassium
Kainate ionotropic Increase membrane permeability for sodium and potassium
NMDA ionotropic Increase membrane permeability for calcium
Metabotropic Group 1 G-coupled proteins Activation 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 ”.[27]

The first uses of quisqualic acid in research date back to 1975,[28] 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.[17] 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.[29] 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.[29][30]

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.[29][31]

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 .[29][32][33]

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.[28] 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) .[28][34]

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.[35]

Quisqualic acid has not been used in clinical trials and currently has no medicinal use,[36] 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.[36]

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.[35] 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.[37] It is also confirmed by using admetSAR tool to evaluate chemical ADMET properties.[35] 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

References

  1. ↑ "Quisqualic acid" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/40539#section=Safety-and-Hazards. 
  2. ↑ "Mechanism of activation and selectivity in a ligand-gated ion channel: structural and functional studies of GluR2 and quisqualate". Biochemistry 41 (52): 15635–15643. December 2002. doi:10.1021/bi020583k. PMID 12501192. 
  3. ↑ "Ion dependence of ligand binding to metabotropic glutamate receptors". Biochemical and Biophysical Research Communications 345 (1): 1–6. June 2006. doi:10.1016/j.bbrc.2006.04.064. PMID 16674916. 
  4. ↑ "The relationship between agonist potency and AMPA receptor kinetics". Biophysical Journal 91 (4): 1336–1346. August 2006. doi:10.1529/biophysj.106.084426. PMID 16731549. Bibcode: 2006BpJ....91.1336Z. 
  5. ↑ "AMPA/Kainate Receptors". Current Pharmaceutical Design 2 (4): 397–412. August 1996. doi:10.2174/1381612802666220925204342. https://books.google.com/books?id=O2ngvw4q5FwC&pg=PA397. 
  6. ↑ "Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention". Behavioural Brain Research 57 (2): 123–131. November 1993. doi:10.1016/0166-4328(93)90128-d. PMID 7509608. 
  7. ↑ "C-fos expression in the rat nucleus basalis upon excitotoxic lesion with quisqualic acid: a study in adult and aged animals". Journal of Neural Transmission 105 (8–9): 935–948. 4 November 1998. doi:10.1007/s007020050103. PMID 9869327. 
  8. ↑ "Prolonged nociceptive responses to hind paw formalin injection in rats with a spinal cord injury". Neuroscience Letters 439 (2): 212–215. July 2008. doi:10.1016/j.neulet.2008.05.030. PMID 18524486. 
  9. ↑ "Geraniums and Begonias: New Research on Old Garden Favorites". Agricultural Research Magazine. March 2010. http://www.ars.usda.gov/is/AR/archive/mar10/garden0310.htm. 
  10. ↑ "Rare excitatory amino acid from flowers of zonal geranium responsible for paralyzing the Japanese beetle". Proceedings of the National Academy of Sciences of the United States of America 108 (4): 1217–1221. January 2011. doi:10.1073/pnas.1013497108. PMID 21205899. Bibcode: 2011PNAS..108.1217R. 
  11. ↑ "Insect Glutamate Receptors". Advances in Insect Physiology 24: 309–341. 1 January 1994. doi:10.1016/S0065-2806(08)60086-7. ISBN 9780120242245. 
  12. ↑ 12.0 12.1 "Combretum indicum (L.) DeFilipps.". Prota 11. Medicinal plants/Plantes médicinales. Wageningen, Netherlands: Pl@ntUse. 2012. https://uses.plantnet-project.org/en/Combretum_indicum_(PROTA). Retrieved 2023-03-19. 
  13. ↑ "Chapter 5 - Five-Membered Heterocycles". The Chemistry of Heterocycles: Nomenclature and Chemistry of Three-to-Five Membered Heterocycles. Netherlands: Elsevier. 2017. ISBN 978-0-08-101033-4. 
  14. ↑ "Subtypes of glutamate Receptors: Pharmacological Classification". CNS neurotransmitters and neuromodulators: glutamate. Boca Raton: CRC Press. 1995. pp. 104. ISBN 978-0-8493-7631-3. 
  15. ↑ "1,2,4-Oxadiazoles" (in en). 4.04 - 1,2,4-Oxadiazoles. Oxford: Pergamon. 1996-01-01. pp. 179–228. doi:10.1016/B978-008096518-5.00082-4. ISBN 978-0-08-096518-5. https://www.sciencedirect.com/science/article/pii/B9780080965185000824. Retrieved 2023-03-19. 
  16. ↑ "Enzymatic synthesis of the neuroexcitatory amino acid quisqualic acid by cysteine synthase" (in en). Phytochemistry 25 (12): 2759–2763. 1986-01-01. doi:10.1016/S0031-9422(00)83736-X. Bibcode: 1986PChem..25.2759M. 
  17. ↑ 17.0 17.1 "Chemoenzymatic Synthesis and Pharmacological Characterization of Functionalized Aspartate Analogues As Novel Excitatory Amino Acid Transporter Inhibitors". Journal of Medicinal Chemistry 61 (17): 7741–7753. September 2018. doi:10.1021/acs.jmedchem.8b00700. PMID 30011368. 
  18. ↑ "Physicochemical Properties for Potential Alzheimer’s Disease Drugs". Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders. Elsevier. 2017. pp. 59–82. 
  19. ↑ 19.0 19.1 "Calcium signaling in neurodegeneration". Molecular Neurodegeneration 4 (1): 20. May 2009. doi:10.1186/1750-1326-4-20. PMID 19419557. 
  20. ↑ "The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death". Annual Review of Neuroscience 13: 171–182. 1990. doi:10.1146/annurev.ne.13.030190.001131. PMID 1970230. 
  21. ↑ "Structural insights into the activation initiation of full-length mGlu1". Protein & Cell 12 (8): 662–667. August 2021. doi:10.1007/s13238-020-00808-5. PMID 33278019. 
  22. ↑ "G proteins: transducers of receptor-generated signals". Annual Review of Biochemistry 56 (1): 615–649. June 1987. doi:10.1146/annurev.bi.56.070187.003151. PMID 3113327. 
  23. ↑ "Activation of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis amplifies NMDA-induced neuronal degeneration in cultured cortical cells". Neuropharmacology 34 (8): 1089–1098. August 1995. doi:10.1016/0028-3908(95)00077-J. PMID 8532158. 
  24. ↑ "Activation of the glutamate metabotropic receptor protects retina against N-methyl-D-aspartate toxicity". European Journal of Pharmacology 219 (1): 173–174. August 1992. doi:10.1016/0014-2999(92)90598-X. PMID 1397046. 
  25. ↑ "Effects of quisqualic acid on retinal ZENK expression induced by imposed defocus in the chick eye" (in en-US). Optometry and Vision Science 81 (2): 127–136. February 2004. doi:10.1097/00006324-200402000-00011. PMID 15127932. https://journals.lww.com/optvissci/Abstract/2004/02000/Effects_of_Quisqualic_Acid_on_Retinal_ZENK.11.aspx. 
  26. ↑ "Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma". Cancer Research 67 (5): 2298–2305. March 2007. doi:10.1158/0008-5472.CAN-06-3665. PMID 17332361. https://aacrjournals.org/cancerres/article/67/5/2298/534739/Metabotropic-Glutamate-Receptor-1-and-Glutamate. 
  27. ↑ "Effects of quisqualic acid analogs on metabotropic glutamate receptors coupled to phosphoinositide hydrolysis in rat hippocampus". Neuropharmacology 34 (8): 829–841. August 1995. doi:10.1016/0028-3908(95)00070-m. PMID 8532164. 
  28. ↑ 28.0 28.1 28.2 "Domoic and quisqualic acids as potent amino acid excitants of frog and rat spinal neurones". Nature 255 (5504): 166–167. May 1975. doi:10.1038/255166a0. PMID 1128682. Bibcode: 1975Natur.255..166B. 
  29. ↑ 29.0 29.1 29.2 29.3 "The mechanosensitivity of spinal sensory neurons following intraspinal injections of quisqualic acid in the rat". Neuroscience Letters 157 (1): 115–119. July 1993. doi:10.1016/0304-3940(93)90656-6. PMID 8233021. 
  30. ↑ "Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model". Pain 75 (1): 141–155. March 1998. doi:10.1016/s0304-3959(97)00216-9. PMID 9539683. 
  31. ↑ "Selective vulnerability of spinal cord motor neurons to non-NMDA toxicity". NeuroReport 11 (5): 1117–1121. April 2000. doi:10.1097/00001756-200004070-00041. PMID 10790892. 
  32. ↑ "The metabotropic excitatory amino acid receptor agonist 1S,3R-ACPD selectively potentiates N-methyl-D-aspartate-induced brain injury". European Journal of Pharmacology 215 (2–3): 353–354. May 1992. doi:10.1016/0014-2999(92)90058-c. PMID 1383003. 
  33. ↑ "Properties of quisqualate-sensitive L-[3H]glutamate binding sites in rat brain as determined by quantitative autoradiography". Journal of Neurochemistry 51 (2): 469–478. August 1988. doi:10.1111/j.1471-4159.1988.tb01062.x. PMID 2899133. 
  34. ↑ "Effects of quisqualic acid and glutamate on subsequent learning, emotionality, and seizure susceptibility in the immature and mature animal". Brain Research 623 (2): 325–328. October 1993. doi:10.1016/0006-8993(93)91447-z. PMID 8106123. 
  35. ↑ 35.0 35.1 35.2 "Quisqualic acid". https://go.drugbank.com/drugs/DB02999. 
  36. ↑ 36.0 36.1 "Traumatic Spinal Cord Injury: An Overview of Pathophysiology, Models and Acute Injury Mechanisms". Frontiers in Neurology 10: 282. 2019-03-22. doi:10.3389/fneur.2019.00282. PMID 30967837. 
  37. ↑ "Responses of detoxification enzymes in the midgut of Bombyx mori after exposure to low-dose of acetamiprid". Chemosphere 251: 126438. July 2020. doi:10.1016/j.chemosphere.2020.126438. PMID 32169693. Bibcode: 2020Chmsp.251l6438W. 



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