Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and in pain management. Ketamine is an NMDA receptor antagonist which accounts for most of its psychoactive effects.
The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ 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.
Opioid-induced hyperalgesia (OIH) or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia, is an uncommon condition of generalized pain caused by the long-term use of high dosages of opioids such as morphine, oxycodone, and methadone. OIH is not necessarily confined to the original affected site. This means that if the person was originally taking opioids due to lower back pain, when OIH appears, the person may experience pain in the entire body, instead of just in the lower back. Over time, individuals taking opioids can also develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). This means that if the person originally felt pain from twisting or from sitting too long, the person might now additionally experience pain from a light touch or from raindrops falling on the skin.
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 humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.
Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder. It is taken orally.
Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.
Rapastinel is a novel antidepressant that was under development by Allergan as an adjunctive therapy for the treatment of treatment-resistant depression. It is a centrally active, intravenously administered amidated tetrapeptide that acts as a novel and selective modulator of the NMDA receptor. The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to enhance NMDA receptor-mediated signal transduction and synaptic plasticity.
ALTO-100, previously known as NSI-189, is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD). There has also been interest in ALTO-100 for possible treatment of cognitive impairment and neurodegeneration. It is taken by mouth.
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.
Aticaprant, also known by its developmental codes JNJ-67953964, CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which is under development for the treatment of major depressive disorder. A regulatory application for approval of the medication is expected to be submitted by 2025. Aticaprant is taken by mouth.
Rislenemdaz is an orally active, selective NMDA receptor subunit 2B (NR2B) antagonist which is under development by Cerecor in the United States as an adjunctive therapy for treatment-resistant depression (TRD). In November 2013, phase II clinical trials were initiated, and in the same month, rislenemdaz received Fast Track Designation from the Food and Drug Administration for TRD.
Arketamine (developmental code names PCN-101, HR-071603), also known as (R)-ketamine or (R)-(−)-ketamine, is the (R)-(−) enantiomer of ketamine. Similarly to racemic ketamine and esketamine, the S(+) enantiomer of ketamine, arketamine is biologically active; however, it is less potent as an NMDA receptor antagonist and anesthetic and thus has never been approved or marketed for clinical use as an enantiopure drug. Arketamine is currently in clinical development as a novel antidepressant.
L-4-Chlorokynurenine is an orally active small molecule prodrug of 7-chlorokynurenic acid, a NMDA receptor antagonist. It was investigated as a potential rapid-acting antidepressant.
Dextromethorphan/bupropion (DXM/BUP), sold under the brand name Auvelity, is a combination medication for the treatment of major depressive disorder (MDD). Its active components are dextromethorphan (DXM) and bupropion. Patients who stayed on the medication had an average of 11% greater reduction in depressive symptoms than placebo in an FDA approval trial. It is taken as a tablet by mouth.
Zelquistinel is an orally active small-molecule NMDA receptor modulator which is under development for the treatment of major depressive disorder (MDD) by Gate Neurosciences, and previously by Allergan.
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.
Tianeptine/naloxone, or naloxone/tianeptine, is an extended-release combination of tianeptine, an atypical μ-opioid receptor agonist, and naloxone, an orally inactive μ-opioid receptor antagonist, which was under development for the treatment of major depressive disorder, post-traumatic stress disorder (PTSD), and neurocognitive dysfunction associated with corticosteroid use but was never marketed.
MSP-1014 is a serotonergic psychedelic which is under development for the treatment of major depressive disorder, other depressive disorders, and anxiety disorders.
