Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.
Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth.
Viloxazine, sold under the brand name Qelbree and formerly as Vivalan among others, is a selective norepinephrine reuptake inhibitor medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken orally. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form.
Mecamylamine is a non-selective, non-competitive antagonist of the nicotinic acetylcholine receptors (nAChRs) that was introduced in the 1950s as an antihypertensive drug. In the United States, it was voluntarily withdrawn from the market in 2009 but was brought to market in 2013 as Vecamyl and eventually was marketed by Turing Pharmaceuticals.
Guanfacine, sold under the brand name Tenex (immediate-release) and Intuniv (extended-release) among others, is an oral alpha-2a agonist medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure. Guanfacine is FDA-approved for monotherapy treatment of ADHD, as well as being used for augmentation of other treatments, such as stimulants. Guanfacine is also used off-label to treat tic disorders, anxiety disorders, and post-traumatic stress disorder (PTSD).
A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine.
The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, consisting entirely of α7 subunits. As with other nicotinic acetylcholine receptors, functional α7 receptors are pentameric [i.e., (α7)5 stoichiometry].
Surinabant (SR147778) is a cannabinoid receptor type 1 antagonist developed by Sanofi-Aventis. It is being investigated as a potential treatment for nicotine addiction, to assist smoking cessation. It may also be developed as an anorectic drug to assist with weight loss, however there are already several CB1 antagonists or inverse agonists on the market or under development for this application, so surinabant is at present mainly being developed as an anti-smoking drug, with possible application in the treatment of other addictive disorders such as alcoholism. Other potential applications such as treatment of ADHD have also been proposed.
Rivanicline is a drug which acts as a partial agonist at neural nicotinic acetylcholine receptors. It is subtype-selective, binding primarily to the α4β2 subtype. It has nootropic effects and was originally developed as a potential treatment for Alzheimer's disease, but a second action that was subsequently found was that it inhibits the production of Interleukin-8 and thus produces an antiinflammatory effect, and so it has also been developed as a potential treatment for ulcerative colitis. Rivanicline also has stimulant and analgesic actions which are thought to be mediated through stimulation of noradrenaline release, and so it could also have other applications. It has been identified as constituent of tobacco as well.
Tebanicline is a potent synthetic nicotinic (non-opioid) analgesic drug developed by Abbott. It was developed as a less toxic analog of the potent poison dart frog-derived compound epibatidine, which is about 200 times stronger than morphine as an analgesic, but produces extremely dangerous toxic side effects. Like epibatidine, tebanicline showed potent analgesic activity against neuropathic pain in both animal and human trials, but with far less toxicity than its parent compound. It acts as a partial agonist at neuronal nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes.
ABT-418 is a drug developed by Abbott, that has nootropic, neuroprotective and anxiolytic effects, and has been researched for treatment of both Alzheimer's disease and ADHD. It acts as an agonist at neural nicotinic acetylcholine receptors, subtype-selective binding with high affinity to the α4β2, α7/5-HT3, and α2β2 nicotinic acetylcholine receptors but not α3β4 receptors ABT-418 was reasonably effective for both applications and fairly well tolerated, but produced some side effects, principally nausea, and it is unclear whether ABT-418 itself will proceed to clinical development or if another similar drug will be used instead.
GTS-21 is a drug that has been shown to enhance memory and cognitive function. It has been studied for its potential therapeutic uses, particularly in the treatment of neurodegenerative diseases and psychiatric disorders.
Pozanicline is a drug developed by Abbott, that has nootropic and neuroprotective effects. Animal studies suggested it useful for the treatment of ADHD and subsequent human trials have shown ABT-089 to be effective for this application. It binds with high affinity subtype-selective to the α4β2 nicotinic acetylcholine receptors and has partial agonism to the α6β2 subtype, but not the α7 and α3β4 subtypes familiar to nicotine. It has particularly low tendency to cause side effects compared to other drugs in the class.
3-( ethynyl)pyridine (MTEP) is a research drug that was developed by Merck & Co. as a selective allosteric antagonist of the metabotropic glutamate receptor subtype mGluR5. Identified through structure-activity relationship studies on an older mGluR5 antagonist MPEP, MTEP has subsequently itself acted as a lead compound for newer and even more improved drugs.
AR-R17779 is a drug that acts as a potent and selective full agonist for the α7 subtype of neural nicotinic acetylcholine receptors. It has nootropic effects in animal studies, but its effects do not substitute for those of nicotine. It has also been studied as a potential novel treatment for arthritis.
PHA-543,613 is a drug that acts as a potent and selective agonist for the α7 subtype of neural nicotinic acetylcholine receptors, with a high level of brain penetration and good oral bioavailability. It is under development as a possible treatment for cognitive deficits in schizophrenia. It reduces excitotoxicity and protects striatal dopaminergic neurons in rat models. It also potentiates cognitive enhancement from memantine, decreases dynorphin release and inhibits GSK-B3.
TC-2216 is a drug developed by Targacept which acts as a partial agonist at neural nicotinic acetylcholine receptors and was researched for the treatment of anxiety and depression. It was unsuccessful as a therapeutic but is still used in pharmacological research as an alpha4beta2-selective antagonist.
WAY-317538 (SEN-12333) is a drug that acts as a potent and selective full agonist for the α7 subtype of neural nicotinic acetylcholine receptors. It was not the most potent compound in the series, but was selected for further development on the basis of its high selectivity over related receptors, ease of synthesis, and good in vivo properties including high oral bioavailability and good brain penetration. It has nootropic and neuroprotective effects in animal studies, and is being investigated as a potential treatment for neurodegenerative and neurocognitive conditions including Alzheimer's disease and schizophrenia.
Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine. It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine. As of late 2019, (2R,6R)-HNK is in clinical trials for the treatment of depression.
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