Serine is an ɑ-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in the human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by the codons UCU, UCC, UCA, UCG, AGU and AGC.
The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
AP5 is a chemical compound used as a biochemical tool to study various cellular processes. It is a selective NMDA receptor antagonist that competitively inhibits the ligand (glutamate) binding site of NMDA receptors. AP5 blocks NMDA receptors in micromolar concentrations.
Ibotenic acid or (S)-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid, also referred to as ibotenate, is a chemical compound and psychoactive drug which occurs naturally in Amanita muscaria and related species of mushrooms typically found in the temperate and boreal regions of the northern hemisphere. It is a conformationally-restricted analogue of the neurotransmitter glutamate, and due to its structural similarity to this neurotransmitter, acts as a non-selective glutamate receptor agonist. Because of this, ibotenic acid can be a powerful neurotoxin, and is employed as a "brain-lesioning agent" through cranial injections in scientific research.
CNQX or cyanquixaline (6-cyano-7-nitroquinoxaline-2,3-dione) is a competitive AMPA/kainate receptor antagonist. Its chemical formula is C9H4N4O4. CNQX is often used in the retina to block the responses of OFF-bipolar cells for electrophysiology recordings.
AP-7 is a selective NMDA receptor (NMDAR) antagonist that competitively inhibits the glutamate binding site and thus activation of NMDAR. It has anticonvulsant effects.
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.
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia.
Tetrazolylglycine is a potent and selective NMDA receptor agonist, stimulating the NMDA receptor with higher potency than either glutamate or NMDA. It is a potent convulsant and excitotoxin and is used in scientific research.
LY-344,545 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as an antagonist for the metabotropic glutamate receptor subtype mGluR5. It is an epimer of another metabotropic glutamate receptor antagonist, the mGluR2/3-selective LY-341,495.
Gavestinel (GV-150,526) was an investigational drug developed by GlaxoSmithKline for acute intracerebral hemorrhage, which in 2001 failed to show an effect in what was at the time, the largest clinical trial in stroke that had been conducted.
Conantokins are a small family of helical peptides that are derived from the venom of predatory marine snails of the genus Conus. Conantokins act as potent and specific antagonists of the N-methyl-D-aspartate receptor (NMDAR). They are the only naturally-derived peptides to do so. The subtypes of conantokins exhibit a surprising variability of selectivity across the NMDAR subunits, and are therefore uniquely useful in developing subunit-specific pharmacological probes.
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.
HA-966 or (±) 3-Amino-1-hydroxy-pyrrolidin-2-one is a molecule used in scientific research as a glycine receptor and NMDA receptor antagonist / low efficacy partial agonist. It has neuroprotective and anticonvulsant, anxiolytic, antinociceptive and sedative / hypnotic effects in animal models. Pilot human clinical trials in the early 1960s showed that HA-966 appeared to benefit patients with tremors of extrapyramidal origin.
Rapastinel (INN) (former developmental code names GLYX-13, BV-102) is a novel antidepressant that is under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant major depressive disorder. It is a centrally active, intravenously administered (non-orally active) amidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) that acts as a selective, weak partial agonist (mixed antagonist/agonist) of an allosteric site of the glycine site of the NMDA receptor complex (Emax ≈ 25%). The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to both inhibit and enhance NMDA receptor-mediated signal transduction.
7-Chlorokynurenic acid (7-CKA) is a tool compound that acts as a potent and selective competitive antagonist of the glycine site of the NMDA receptor. It produces ketamine-like rapid antidepressant effects in animal models of depression. However, 7-CKA is unable to cross the blood-brain-barrier, and for this reason, is unsuitable for clinical use. As a result, a centrally-penetrant prodrug of 7-CKA, 4-chlorokynurenine (AV-101), has been developed for use in humans, and is being studied in clinical trials as a potential treatment for major depressive disorder, and anti-nociception. In addition to antagonizing the NMDA receptor, 7-CKA also acts as a potent inhibitor of the reuptake of glutamate into synaptic vesicles, an action that it mediates via competitive blockade of vesicular glutamate transporters.
Apimostinel is an antidepressant, acting as a selective partial agonist of an allosteric site of the glycine site of the NMDA receptor complex, which is under investigation by Naurex and Allergan for the treatment of major depressive disorder (MDD). As of 2015, an intravenous formulation of apimostinel is in a phase II clinical trial for MDD, and an oral formulation is concurrently in phase I trials for MDD.
A glycine receptor antagonist is a drug which acts as an antagonist of the glycine receptor.
Licostinel (INN) is a competitive, silent antagonist of the glycine site of the NMDA receptor. It was under investigation by Acea Pharmaceuticals as a neuroprotective agent for the treatment of cerebral ischemia associated with stroke and head injuries but was ultimately never marketed. In clinical trials, licostinel did not produce phencyclidine-like psychotomimetic effects at the doses tested, though transient sedation, dizziness, and nausea were observed. In addition to its actions at the NMDA receptor, licostinel also acts as an antagonist of the AMPA and kainate receptors at high concentrations.
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