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| Routes of administration | Oral |
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| ECHA InfoCard | 100.056.284 |
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| Formula | C15H18ClNO3 |
| Molar mass | 295.76 g·mol−1 |
Enilospirone (CERM-3,726) is a selective 5-HT1A receptor agonist of the azapirone class. [1]
Base catalyzed Williamson ether synthesis between 2-chlorocyclohexanone [822-87-7] (1) and 3-Chlorophenol [108-43-0] (2) gives 2-(3-Chlorophenoxy)cyclohexan-1-one [59798-91-3] (3). Condensation with lactic acid (4) and ammonium carbonate gives Enilospirone (5).
Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).
Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. Benefits support its short-term use. It is taken by mouth, and it may take up to four weeks to have an effect.
Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.
The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is short for 5-hydroxy-tryptamine or serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. Later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones.
Ipsapirone is a selective 5-HT1A receptor partial agonist of the piperazine and azapirone chemical classes. It has antidepressant and anxiolytic effects. Ipsapirone was studied in several placebo-controlled trials for depression and continues to be used in research.
A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.
Tandospirone is an anxiolytic and antidepressant drug used in China and Japan, where it is marketed by Dainippon Sumitomo Pharma. It is a member of the azapirone class of drugs and is closely related to other azapirones like buspirone and gepirone.
5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).
The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) The 5-HT7 receptor is coupled to Gs (stimulates the production of the intracellular signaling molecule cAMP) and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels. This receptor has been a drug development target for the treatment of several clinical disorders. The 5-HT7 receptor is encoded by the HTR7 gene, which in humans is transcribed into 3 different splice variants.
Zalospirone (WY-47,846) is a selective 5-HT1A partial agonist of the azapirone chemical class. It was found to be effective in the treatment of anxiety and depression in clinical trials, but a high proportion of subjects dropped out due to side effects and development was subsequently never completed.
Jimscaline is a conformationally-restricted derivative of the cactus-derived hallucinogen mescaline, which was discovered in 2006 by a team at Purdue University led by David E. Nichols. It acts as a potent agonist for the 5-HT2A and 5-HT2C receptors with the more active (R)-enantiomer having a Ki of 69 nM at the human 5-HT2A receptor, and around three times the potency of mescaline in drug-substitution experiments in animals. This discovery that the side chain of the phenethylamine hallucinogens could be constrained to give chiral ligands with increased activity then led to the later development of the super-potent benzocyclobutene derivative TCB-2.
Alnespirone (S-20,499) is a selective 5-HT1A receptor full agonist of the azapirone chemical class. It has antidepressant and anxiolytic effects.
Oxaflozane (INN) is an antidepressant and anxiolytic drug that was introduced by Solvay in France in 1982 for the treatment of depression but has since been discontinued. It is a prodrug of flumexadol, which is reported to act as an agonist of the serotonin 5-HT1A and 5-HT2C receptors and, to a much lesser extent, of the 5-HT2A receptor. In addition to its serotonergic properties, oxaflozane may also produce anticholinergic side effects at high doses, namely in overdose.
Eptapirone (F-11,440) is a very potent and highly selective 5-HT1A receptor full agonist of the azapirone family. Its affinity for the 5-HT1A receptor was reported to be 4.8 nM (Ki), and its intrinsic activity approximately equal to that of serotonin.
Tiospirone (BMY-13,859), also sometimes called tiaspirone or tiosperone, is an atypical antipsychotic of the azapirone class. It was investigated as a treatment for schizophrenia in the late 1980s and was found to have an effectiveness equivalent to those of typical antipsychotics in clinical trials but without causing extrapyramidal side effects. However, development was halted and it was not marketed. Perospirone, another azapirone derivative with antipsychotic properties, was synthesized and assayed several years after tiospirone. It was found to be both more potent and more selective in comparison and was commercialized instead.
Revospirone is an azapirone drug which was patented as a veterinary tranquilizer but was never marketed. It acts as a selective 5-HT1A receptor partial agonist. Similarly to other azapirones such as buspirone, revospirone produces 1-(2-pyrimidinyl)piperazine (1-PP) as an active metabolite. As a result, it also acts as an α2-adrenergic receptor antagonist to an extent.
Umespirone (KC-9172) is a drug of the azapirone class which possesses anxiolytic and antipsychotic properties. It behaves as a 5-HT1A receptor partial agonist (Ki = 15 nM), D2 receptor partial agonist (Ki = 23 nM), and α1-adrenoceptor receptor antagonist (Ki = 14 nM), and also has weak affinity for the sigma receptor (Ki = 558 nM). Unlike many other anxiolytics and antipsychotics, umespirone produces minimal sedation, cognitive/memory impairment, catalepsy, and extrapyramidal symptoms.
Lesopitron (E-4424) is a selective full agonist of the 5-HT1A receptor which is structurally related to the azapirones. In 2001 it was under development by Esteve as an anxiolytic for the treatment of generalized anxiety disorder (GAD). It made it to phase II clinical trials but was apparently discontinued as no new information on lesopitron has surfaced since.
Osemozotan (MKC-242) is a selective 5-HT1A receptor agonist with some functional selectivity, acting as a full agonist at presynaptic and a partial agonist at postsynaptic 5-HT1A receptors. 5-HT1A receptor stimulation influences the release of various neurotransmitters including serotonin, dopamine, norepinephrine, and acetylcholine. 5-HT1A receptors are inhibitory G protein-coupled receptor. Osemozotan has antidepressant, anxiolytic, antiobsessional, serenic, and analgesic effects in animal studies, and is used to investigate the role of 5-HT1A receptors in modulating the release of dopamine and serotonin in the brain, and their involvement in addiction to abused stimulants such as cocaine and methamphetamine.
Flumexadol (INN) is a drug described and researched as a non-opioid analgesic which was never marketed. It has been found to act as an agonist of the serotonin 5-HT1A and 5-HT2C receptors and, to a much lesser extent, of the 5-HT2A receptor. According to Nilsson (2006) in a paper on 5-HT2C receptor agonists as potential anorectics, "The (+)-enantiomer of this compound showed [...] affinity for the 5-HT2C receptor (Ki) 25 nM) [...] and was 40-fold selective over the 5-HT2A receptor in receptor binding studies. Curiously, the racemic version [...], also known as 1841 CERM, was originally reported to possess analgesic properties while no association with 5-HT2C receptor activity was mentioned." It is implied that flumexadol might be employable as an anorectic in addition to analgesic. Though flumexadol itself has never been approved for medical use, oxaflozane is a prodrug of the compound that was formerly used clinically in France as an antidepressant and anxiolytic agent.
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