Overview Of NMDA Receptors As Drug Targets In CNS Therapeutics

Structure and Function of NMDA Receptors

Give an overview of the NMDA receptors as drug targets in the CNS therapeutics?

NMDA receptors are named based on N-methyl-D-aspartate (selective agonist). This N-methyl-D-aspartate belongs to the ionotropic glutamate receptor family. These receptors are heterotetramers, which include GluN2A-D, GluN1 and GluN3A-B. From previous studies, it is found that NMDA receptor reported to have splice variants; however, most of the studies were performed on GluN1 subunit, which have 8 different isomers. It is observed that the amino acid glutamates intervene throughout the spinal cord and brain, the extensive majority of “excitatory neurotransmission”. According to Pierre et al. (2013), Glutamate can act on different membrane receptors, which include ionotropic glutamate receptors (iGluRs). These ionotropic glutamate receptors can further form cation permeable ion channel receptors and therefore can be divided into three major groups, such as NMDA receptors (NMDARs), AMPA receptors (AMPARs) and kainite receptors. As NMDARs plays a key role in the function of CNS, it takes the concentrations of the neuroscientists. These glutamate gated ion channels are necessary to mediate brain plasticity and these channels have the ability to convert the specific neuronal activity pattern to long-term modification in the functions and the structure of the synapse. Dysfunction of NMDAR is directly involved in the different psychiatric and neurological disorders, which includes neurodegenerative diseases, pathological pains, stroke and schizophrenia. Consequently, there is an increasing interest to develop new drugs targeting these receptors. From the recent studies it is observed that NMDARs have a extensive diversity in their functions. A huge diversity is found among the NMDARs, such as diversity in the molecular composition, the pharmacological and biophysical properties of NMDARs, the subcellular localization of the molecules and the interacting partners of NMDARs. The subunit composition may vary across CNS regions, while the person is in a state of disease. From researches it was also evident that in the fully matured synapse, the subunit content of the NMDAR could be changed depending on the activity of the neurons. According to Pierre et al. (2013), the individual roles of the different NMDAR subtypes are able to help to define different strategies to act against the deleterious effects of the function of deregulated NMDAR. On the other hand, Brendan et al. (2012) supported the statements of Pierre et al. (2013) and mentioned that NMDARs play a key or major role during pathophysiological and physiological conditions of the mammals. These NMADARs are permeable to the Ca²⁺ ion, which is responsible for the most of the excitatory neural transmission in the “Central Nervous System” (CNS). These NMADARs also plays a key role in the regulation of neural development, glutamate induced neurotoxicity and the synaptic plasticity. Implication of NMADARs dysfunction in various CNS pathologies usually includes neurodegenerative diseases, ischemic stroke as well as traumatic brain injury. Glutamate-induced neurotoxicity theory is focused on the neuronal death mechanism, which may be the reason behind different types of CNS injuries. From the previous researches it is observed that the occurrence of neurotoxicity due to the glutamate may take place because of the overreaction of “glutamate receptors”. It is found that NMADARs influences the permeability of Ca2⁺, which is further induced by the increase release of extracellular glutamate (Swinney and Anthony 2011). This phenomenon is completely responsible for the triggering of neuronal death incidents (Melancon et al. 2012). On the other hand, the molecular structures of NMADARs are widely known as heteromeric tetramers (Wallace et al. 2011). As previously discussed, Brendan et al. (2012), the structure of NMADARs includes GluN2 (A-D), GluN3 (A-B) and an obligate subunit, GluN1. When agonist glutamate binds up with the GluN2 subunit and co-agonist glycine binds with the GluN1 subunit, the receptors are activated. The bindings of the subunits with the substrates trigger the pertinent cation second messenger Ca²⁺ through the “channel pore” (Gregory et al. 2011).  The most common subtypes of CNS found in mammals are GluN2ARs (GluN2A-comtaining NMDARs) and GluN2BRs (GluN2B-comtaining NMDARs) (Vinson and Conn 2012). From the previous researches it was observed that NMDARs receptors have different functions.

Role of NMDA Receptors in CNS Pathologies

According to Brendan et al. (2012), these differences may feature the distinct combinations of the subunits. This is because the subunits show different functional properties based on Electrophysiology as well as various sensitivities to the regulation depending on the intracellular signals (de Lange 2013). It is observed that pharmacological antagonists, which target NMDARs, were experimented in the laboratories. However, the results were not fruitful while treating different states of CNS diseases. May be the reasons behind these possible failures of those experiments is the function of NMDARs on both cell-death signaling and cell-survival signaling. Therefore, it is observed that the nonspecific inhibition of the NMDARs blocked the pathways of the neuronal death as well as inhibiting the pro - survival signaling. According to the researchers, many intracellular and extracellular processes are known to modulate NMDARs, dephosphorylation and the phosphosphorylation using protein phosphatases and kinases are very important, since these factors are capable to regulate the channel properties, surface expression and the trafficking of NMDARs (Duman and Aghajanian 2012). From researches it is also found that one can target intracellular pathways, which may be under the government of NMDARs, can offer a heavier mechanistic basis that in turn can help in the survival of cells during CNS injury. Over time, the researchers discussed about the roles of GluN2BRs and GluN2ARs in the context of death and survival of neurons (Macrez et al. 2011). The importance of these two subunits over the intracellular signal chain, which are initiated by individual receptor subtypes.

It is observed that the NMDAR subunits have a similar structure like kainate receptor and AMPA. The ABD and NTD are two extracellular domains are similar to the bacterial periplasmic proteins (de Lange 2013). On the other hand, the NR1 subunit can be expressed in all brain cells, but the expression of NR2B is prohibited in the NR2B expression. It is observed that one of the potent inhibitor of NMDA is extracellular protons. These extracellular protons inhibit the NMDARs by using voltage independent and non-competitive manner, which indicates that they do not act as channel blockers. On the other hand, it is observed that NR2B act as a selective “positive allosteric modulators” (Swinney and Anthony 2011). These are the possible ways by which NMDARs targets in the CNS. As previously mentioned, the NMDA receptor is considered as the ionotropic receptor, which allows the necessary signals between the spinal column and the brain cells (neurons of the brain) (Cevikbas, Steinhoff and Ikoma 2011). To pass the signals it is necessary that the channels of the NMDARs should remain open. However, it is observed that to open the NMDARs chain there are several factors. First of all, to remain open the NMDARs signaling system, it is important that glycine and glutamate should be bound up with the NMDA receptors. When an NMDA receptor is attached with a glutamate and a glycine molecule, it became open or activated and started transferring signals between the spinal column and brain (Duman and Aghajanian 2012). On the other hand, the antagonists are the blockers that target the NMDA in the CNS. As previously mentioned, these antagonists can be divided into four major groups such as competitive antagonists, noncompetitive antagonists, uncompetitive antagonists and the glycine antagonists. In the competitive antagonist mechanism, competitive antagonists compete with the glutamate to bind up with the NMDAR, in the substrate site (Cevikbas, Steinhoff and Ikoma 2011). There are many competitive antagonists such as AP5 (APV, R-2-amino-5-phosphonopentanoate), Selfotel (anxiolytic with potential neurotoxic effect), CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid) and AP7 (2-amino-7-phosphonoheptanoic acid). It is observed that these competitive units has more attraction to the binding site than glutamate itself, which in turn thrown out glutamate from the competition and blocks the signaling. There are also some glycine antagonists such as Rapastinel (GLYX-13), 7-Chlorokynurenic acid, Kyneurenic acid, TK-40, ACPC (1-Aminocyclopropanecarboxylic acid), which competes with the glutamate over binding site and attached on another binding site thus blocking the binding site of the NMDARs (Dzamba, Honsa and Anderova 2013). The mechanism used by the non-competitive antagonists is almost same as the glycine antagonists. In non-competitive antagonistic method, the noncompetitive antagonist binds at the allosteric sites of the NMDAR and therefore blocks the site of glutamate (Lujan, Liu and Wan 2012). The names of the few noncompetitives are Aptiganel (Cerestat, CNS-1102), HU-211, Remacemide and Ketamine (Kalivas and Volkow 2011). It is observed that ketamine is hugely used in the antidepressant and used as an anesthesia; therefore, the use of antidepressant is not good for health (Vinson and Conn 2012). On the other hand, the uncompetitive antagonists are used to block the ion channel. The uncompetitive antagonists bind up to the site within the molecule and block the ion channel (Dzamba, Honsa and Anderova 2013). Some of the popular uncompetitive antagonists are Amantidine, Atomoxetine, Agmatine, chloroform, dextrophan, Tiletamine, Delucemine, etc. Among these antagonists, Amantidine is commonly used to treat influenza, Alzheimer and Parkinson’s disease (Gregory et al. 2011). On the other hand, Agmatine not only blocks NMDRs but also blocks other metabolic channels, which are cation ligand-gated. However, Tiletamine is considered as an animal anesthetic (Ogden and Traynelis 2011).

Diversity of NMDA Receptors and Subunit Composition

From previous studies it is observed that different NMDAR subtypes play different key roles. Based on the latest researches it can be said that the subtype selective modulations of the NMDRs function can provide promising therapeutic prospective in the treatment of a vast range of CNS disorders (Lujan, Liu and Wan 2012). Therefore, NR2B selective antagonists could be used in the treatment of CNS disorders, which include Alzheimer’s disease, Parkinsons disease, Huntington’s disease, major depression and cerebral ischemia. However, the non-selective antagonists may generate different side effects such as cardiovascular, behavioral as well as cytotoxic activities (Paoletti, Bellone and Zhou 2013). Due to these side effects, non- selective NMDAR antagonists have limited therapeutic development. Selective NMDAR antagonists such as dextromethorphan, and Ketamine have a broad-spectrum effect (Ogden and Traynelis 2011). These are used to treat neuropathic pain. However, they have narrow therapeutic index, since the patients’ experiences inevitable side effects. On the other hand, the availability of the NR2B selective antagonists helps to increase the validity of NMDARs, which contain NR2B as a potential target in the treatment of neuropathic pain. These agents even have the reputation to treat chronic and acute inflammatory and visceral pain (Dzamba, Honsa and Anderova 2013). On the other hand, it was observed that NMDARs play a positive role to develop dyskinesia, which is induced by levodopa (Mony et al. 2009). When the researchers started investigating about the therapeutic potentiality of NMDAR antagonists, they observed that the antagonists can show antidyskinetic or antiparkinsonian activity in rodents as well as in monkey. From latest researches, it is also found that amantidine, which is a NMDAR antagonist with low affinity can shows antidyskinetic or antiparkinsonian activity in human. NR2B selective antagonists also showed efficacy to treat Parlinsonism in both primates (non-human) and rodents (Paoletti, Bellone and Zhou 2013). The Huntington’s disease is the result of the mutant expression of huntingtin gene. From the research it is found that Huntington’s disease causes excitotoxic damage as well as concerned the NMDAR dysregulation (Lujan, Liu and Wan 2012). However, it is observed that NR2B containing receptors showed a little enhancement in the treatment. In the USA and in Europe, the broad spectrum (with low affinity) NMDAR channel blocker “memantine” is approved for the treatment of Alzheimer’s disease (in both moderate and severe cases) (Monaghan et al. 2012). The memantine is used as cognitive enhancing therapy as it is observed that NMDAR plays a key role in reserving memory and learning. The CNS glutamate receptors, particularly the NMDARs, which are highly Ca²⁺ permeable, help in the treatment of cerebral ischemia as well as in traumatic brain injury. On the other hand, broad spectrum NMDAR is also used in the treatment of major depression cases. Ketamine a NMDAR channel blocker is extensively used in the treatment of depression. However, due to the psychometric effect of the ketamine, the use is limited (Monaghan et al, 2012). In addition, NR2B selective antagonists also showed antidepressant activity in the treatment of major depression.  

References

Cevikbas, F., Steinhoff, M. and Ikoma, A., 2011. Role of spinal neurotransmitter receptors in itch: new insights into therapies and drug development. CNS neuroscience & therapeutics, 17(6), pp.742-749.

de Lange, E.C., 2013. The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects. Fluids Barriers CNS, 10(1), p.12.

Duman, R.S. and Aghajanian, G.K., 2012. Synaptic dysfunction in depression: potential therapeutic targets. Science, 338(6103), pp.68-72.

Dzamba, D., Honsa, P. and Anderova, M., 2013. NMDA receptors in glial cells: pending questions. Current neuropharmacology, 11(3), p.250.

Gregory, K.J., Dong, E.N., Meiler, J. and Conn, P.J., 2011. Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology, 60(1), pp.66-81.

Kalivas, P.W. and Volkow, N.D., 2011. New medications for drug addiction hiding in glutamatergic neuroplasticity. Molecular psychiatry, 16(10), pp.974-986.

Lujan, B., Liu, X. and Wan, Q., 2012. Differential roles of GluN2A-and GluN2B-containing NMDA receptors in neuronal survival and death.International journal of physiology, pathophysiology and pharmacology, 4(4), p.211.

Macrez, R., Ali, C., Toutirais, O., Le Mauff, B., Defer, G., Dirnagl, U. and Vivien, D., 2011. Stroke and the immune system: from pathophysiology to new therapeutic strategies. The Lancet Neurology, 10(5), pp.471-480.

Melancon, B.J., Hopkins, C.R., Wood, M.R., Emmitte, K.A., Niswender, C.M., Christopoulos, A., Conn, P.J. and Lindsley, C.W., 2012. Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. Journal of medicinal chemistry, 55(4), pp.1445-1464.

Monaghan, D.T., Irvine, M.W., Costa, B.M., Fang, G. and Jane, D.E., 2012. Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators. Neurochemistry international,61(4), pp.581-592

Mony, L., Kew, J., Gunthorpe, M. and Paoletti, P. (2009). Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential. British Journal of Pharmacology, 157(8), pp.1301-1317.

Ogden, K.K. and Traynelis, S.F., 2011. New advances in NMDA receptor pharmacology. Trends in pharmacological sciences, 32(12), pp.726-733.

Paoletti, P., Bellone, C. and Zhou, Q., 2013. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.Nature Reviews Neuroscience, 14(6), pp.383-400.

Swinney, D.C. and Anthony, J., 2011. How were new medicines discovered?. Nature reviews Drug discovery, 10(7), pp.507-519.

Vinson, P.N. and Conn, P.J., 2012. Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology, 62(3), pp.1461-1472.

Wallace, T.L., Ballard, T.M., Pouzet, B., Riedel, W.J. and Wettstein, J.G., 2011. Drug targets for cognitive enhancement in neuropsychiatric disorders.Pharmacology Biochemistry and Behavior, 99(2), pp.130-145.