BMY-14802, also known as BMS-181100, is a drug with antipsychotic effects which acts as both a sigma receptor antagonist and a 5-HT1A receptor agonist.
It also has affinity for the 5-HT2 and D4 receptors.
The drug reached phase III clinical trials for the treatment of psychosis but was never marketed.
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Blonanserin, sold under the brand name Lonasen, is a relatively new atypical antipsychotic (approved by PMDA in January 2008) commercialised by Dainippon Sumitomo Pharma in Japan and Korea for the treatment of schizophrenia. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension. As with many second-generation (atypical) antipsychotics it is significantly more efficacious in the treatment of the negative symptoms of schizophrenia compared to first-generation (typical) antipsychotics such as haloperidol.
Medical Uses
Blonanserin is used to treat schizophrenia in Japan and South Korea but not in the US.
Adverse Effects
As with many of the atypical antipsychotics, blonanserin can elicit cardio metabolic risks. While the side effects of blonanserin – such as weight gain, cholesterol and triglyceride levels, glucose levels and other blood lipid levels – do not differ greatly from other atypical antipsychotics, the specificity of blonanserin appears to elicit milder side effects, with less weight gain in particular.
Pharmacology
Pharmacodynamics
Blonanserin acts as a mixed 5-HT2A (Ki = 0.812 nM) and D2 receptor (Ki = 0.142 nM) antagonist and also exerts some blockade of α1-adrenergic receptors (Ki = 26.7 nM). Blonanserin also shows significant affinity for the D3 receptor (Ki = 0.494 nM). It lacks significant affinity for numerous other sites including the 5-HT1A, 5-HT3, D1, α2-adrenergic, β-adrenergic, H1, and mACh receptors and the monoamine transporters, though it does possess low affinity for the sigma receptor (IC50 = 286 nM).
Blonanserin has a relatively high affinity towards the 5-HT6 receptor perhaps underpinning its recently unveiled efficacy in treating the cognitive symptoms of schizophrenia. The efficacy of blonanserin can in part be attributed to its chemical structure, which is unique from those of other atypical antipsychotics. Specifically, the addition of hydroxyl groups to blonanserin’s unique eight membered ring results in the (R) stereoisomer of the compound demonstrating increased affinity for the indicated targets.
Action at the Dopamine-D3 Receptor
Blonanserin has antagonistic action at dopamine-D3 receptors that potentiates phosphorylation levels of Protein kinase A (PKA) and counteracts decreased activity at the dopamine-D1 and/or NMDA receptors, thus potentiating GABA induced Cl- currents. Olanzapine does not appear to affect PKA activity. Many antipsychotics, such as haloperidol, chlorpromazine, risperidone and olanzapine primarily antagonise serotonin 5-HT2A and dopamine-D2 receptors and lack known action at dopamine-D2/3 receptors.
Pharmacokinetics
Blonanserin is administered 4 mg orally twice a day or 8 mg once a day, for an adult male with a body mass index between 19–24 kg/m2 and a body weight equal to or greater than 50 kg. The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination. The half-life of blonanserin is dependent on the dose. A single dose of 4 mg has a half-life of 7.7 ± 4.63 h and a single dose of 8 mg has a half-life of 11.9 ± 4.3 h. The increase of half-life with dose is possibly attributed to there being more individual concentration per time points below the lower limit necessary for quantification in the lower single dose.
Blonanserin is not a charged compound and exhibits very little chemical polarity. The polar surface area of Blonanserin is 19.7 Å It is commonly accepted that a compound needs to have polar surface area less than 90 Å to cross the blood brain barrier so blonanserin is expected to be quite permeable as is demonstrated by a high brain/ plasma ratio of 3.88.
Due to the good permeability of blonanserin, the volume of distribution in the central nervous system is greater than that in the periphery (Vd central = 9500 L, Vd periphery = 8650 L) although it is slower to absorb into the central compartment.
Blonanserin does not meet the criteria in Lipinski’s rule of five.
Effects of Food Intake
Food intake slows the absorption of blonanserin and increases the bioavailability peripherally relative to centrally. Single fasting doses are safe and the effects of feeding intake are possibly explained by an interaction between blonanserin and cytochrome P450 3A4 in the gut.
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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) (or 8.33 (pKi)), and its intrinsic activity approximately equal to that of serotonin (i.e. 100%).
Eptapirone and related high-efficacy 5-HT1A full and super agonists such as befiradol and F-15,599 were developed under the hypothesis that the maximum exploitable therapeutic benefits of 5-HT1A receptor agonists might not be able to be seen without the drugs employed possessing sufficiently high intrinsic activity at the receptor. As 5-HT1A receptor agonism, based on animal and other research, looked extremely promising for the treatment of depression from a theoretical perspective, this idea was developed as a potential explanation for the relatively modest clinical effectiveness seen with already available 5-HT1A receptor agonists like buspirone and tandospirone, which act merely as weak-to-moderate partial agonists of the receptor.
Animal Studies
In the Porsolt forced swimming test, eptapirone was found to suppress immobility more robustly than buspirone, ipsapirone, flesinoxan, paroxetine, and imipramine, which was suggestive of strong antidepressant-like effects. In this assay, unlike the other drugs screened, buspirone actually increased the immobility time with a single administration, while repeated administration decreased it, an effect that may have been related to buspirone’s relatively weak intrinsic activity (~30%) at the 5-HT1A receptor and/or its preferential activation of 5-HT1A somatodendritic autoreceptors over postsynaptic receptors.
After repeated administration, high dose paroxetine was able to rival the reduction in immobility seen with eptapirone. However, efficacy was seen on the first treatment with eptapirone, which suggested that eptapirone may have the potential for a more rapid onset of antidepressant effectiveness in comparison. Imipramine was unable to match the efficacy of eptapirone or high dose paroxetine, which was probably the result of the fact that higher doses were fatal.
In the conflict procedure, eptapirone produced substantial increases in punished responding without affecting unpunished responding, which was suggestive of marked anxiolytic-like effects. In addition, the efficacy of eptapirone in this assay was more evident than that of buspirone, ipsapirone, and flesinoxan.
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Flesinoxan (DU-29,373) is a potent and selective 5-HT1A receptor partial/near-full agonist of the phenylpiperazine class. Originally developed as a potential antihypertensive drug, flesinoxan was later found to possess antidepressant and anxiolytic effects in animal tests.
As a result, it was investigated in several small human pilot studies for the treatment of major depressive disorder, and was found to have robust effectiveness and very good tolerability. However, due to “management decisions”, the development of flesinoxan was stopped and it was not pursued any further.
In patients, flesinoxan enhances REM sleep latency, decreases body temperature, and increases ACTH, cortisol, prolactin, and growth hormone secretion.
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Befiradol (F-13,640; NLX-112) is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.
Brief History
Befiradol was discovered and developed by Pierre Fabre Médicament, a French pharmaceuticals company who initially developed it as a treatment for chronic pain. In September 2013, befiradol was out-licensed to Neurolixis, a US-based biotechnology company. Neurolixis announced that it intended to re-purpose befiradol for the treatment of levodopa-induced dyskinesia in Parkinson’s disease. In support of this indication, Neurolixis received several research grants from the Michael J. Fox Foundation and preclinical data was published describing the activity of befiradol in animal models of Parkinson’s disease. Studies published in 2020 using non-human primate models of Parkinson’s disease, (MPTP-treated marmosets and MPTP-treated macaques), found that befiradol potently reduced Levodopa-induced dyskinesia at oral doses as low as 0.1 to 0.4 mg/kg. In January 2018, the British charity Parkinson’s UK announced that it had awarded Neurolixis a grant to advance development of befiradol up to clinical phase in Parkinson’s disease patients.
Pharmacology
In recombinant cell lines expressing human 5-HT1A receptors, befiradol exhibits high agonist efficacy for a variety of signal transduction read-outs, including ERK phosphorylation, G-protein activation, receptor internalisation and adenylyl cyclase inhibition. In rat hippocampal membranes it preferentially activates GalphaO proteins. In neurochemical experiments, befiradol activated 5-HT1A autoreceptors in rat dorsal Raphe nucleus as well as 5-HT1A heteroreceptors on pyramidal neurons in the frontal cortex. In rat models, it has powerful analgesic and antiallodynic effects comparable to those of high doses of opioid painkillers, but with fewer and less prominent side effects, as well as little or no development of tolerance with repeated use.
A structure–activity relationship (SAR) study revealed that replacement of the dihalophenyl moiety by 3-benzothienyl increases maximal efficacy from 84% to 124% (Ki=2.7 nM).
Clinical Ph2A Trial for Dyskinesia in Parkinson’s Disease
In March 2019, Neurolixis announced that the US Food and Drug Administration (FDA) gave a positive response to Neurolixis’ Investigational New Drug (IND) application for NLX-112 to be tested in a Phase 2 clinical study in Parkinson’s disease patients with troublesome levodopa-induced dyskinesia. On 22 November 2020, The Sunday Times reported that the two charities, Parkinson’s UK and Michael J. Fox Foundation, were jointly investing $2 million to support a clinical trial on befiradol in Parkinson’s disease patients with troublesome Levodopa-induced dyskinesia, a potentially “life changing” drug. On 23 November 2020, Parkinson’s UK and Michael J. Fox Foundation, confirmed their funding in an official announcement. Neurolixis announced on 30 November 2021 the start of patient recruitment in the clinical trial. The trial is listed on the US National Library of Medicine clinical trials register. On 20 March 2023, a joint press release from Neurolixis, Parkinson’s UK and Michael J. Fox Foundation announced that the clinical trial had met its primary endpoint of safety and tolerability, and also the secondary endpoint of efficacy in reducing Levodopa-induced dyskinesia in the patients. Moreover, a later announcement (07 July 2023) disclosed that the clinical trial had also found that befiradol reduced parkinsonism symptoms (such as slowness of movement, tremor and rigidity), as well as Levodopa-induced dyskinesia, raising the prospect of developing a “dual-efficacy therapy” for Parkinson’s disease.
18F-Befiradol as an Agonist PET Radiotracer for Brain Imaging
As well as studies on befiradol for treatment of movement disorders, other researchers have investigated it as a novel radiotracer for brain imaging studies by positron emission tomography. Thus befiradol labeled with [18F] (also known as 18F-F13640) has been used to study the distribution of serotonin 5-HT1A receptors in rat, cat, macaque and human. Because befiradol is an agonist, it enables the detection of 5-HT1A receptors which are specifically in a functionally active state, whereas antagonist radiotracers label the total receptor population.
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Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome (CDS). It may be used alone or along with stimulant medication. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time, and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.
Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. There is a lack of data regarding its safety during pregnancy; as of 2019, its safety during pregnancy and for use during breastfeeding is not certain.
It was approved for medical use in the US in 2002. In 2022, it was the 213th most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Brief History
Atomoxetine is manufactured, marketed, and sold in the United States as the hydrochloride salt (atomoxetine HCl) under the brand name Strattera by Eli Lilly and Company, the original patent-filing company and current US patent owner. Atomoxetine was initially intended to be developed as an antidepressant, but it was found to be insufficiently efficacious for treating depression. It was, however, found to be effective for ADHD and was approved by the US Food and Drug Administration (FDA) in 2002, for the treatment of ADHD. Its patent expired in May 2017. On 12 August 2010, Lilly lost a lawsuit that challenged its patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. On 01 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the US. In a 29 July 2011 conference call, however, Sun Pharmaceutical’s Chairman stated “Lilly won that litigation on appeal so I think [generic Strattera]’s deferred.”
In 2017, the FDA approved the generic production of atomoxetine by four pharmaceutical companies.
Medical Uses
Atomoxetine is indicated for the treatment of ADHD.
Attention Deficit Hyperactivity Disorder
Atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. One of the primary differences with the standard stimulant treatments for ADHD is that it has little known abuse potential. Meta-analyses and systematic reviews have found that atomoxetine has comparable efficacy and equal tolerability to methylphenidate in children and adolescents. In adults, efficacy and tolerability are equivalent.
While its efficacy may be less than that of lisdexamphetamine, there is some evidence that it may be used in combination with stimulants. Doctors may prescribe non-stimulants including atomoxetine when a person has bothersome side effects from stimulants; when a stimulant was not effective; in combination with a stimulant to increase effectiveness; when the cost of stimulants is prohibitive; or when there is concern about the abuse potential of stimulants in a patient with a history of substance use disorder.
Atomoxetine alleviates ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine in the prefrontal cortex, sharing 70-80% of the brain regions with stimulants in their produced effects.
Unlike α2-adrenergic receptor agonists such as guanfacine and clonidine, atomoxetine’s use can be abruptly stopped without significant withdrawal symptoms being observed.
The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent. A further 2 to 4 weeks may be required for the full therapeutic effects to be seen. Incrementally increasing response may occur up to 1 year or longer. The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.
Other Uses
Cognitive Disengagement Syndrome
Atomoxetine may be used to treat cognitive disengagement syndrome (CDS), as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment. In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.
Traumatic Brain Injury
Atomoxetine is sometimes used in the treatment of cognitive impairment and frontal lobe symptoms due to conditions like traumatic brain injury (TBI). It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition, lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome. A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects. Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid haemorrhage in a case report.
Common side effects include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. A 2020 meta-analysis found that atomoxetine was associated with anorexia, weight loss, and hypertension, rating it as a “potentially least preferred agent based on safety” for treating ADHD. As of 2019, safety in pregnancy and breastfeeding is not clear; a 2018 review stated that, “[b]ecause of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy.”
The US Food and Drug Administration (FDA) has issued a black box warning for suicidal behaviour/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.
Overdose
Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death.
Interactions
Atomoxetine is a substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree.
Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6.3 μM, which has the potential to cause arrhythmia. QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolisers.
Other notable drug interactions include:
Antihypertensive agents, due to atomoxetine acting as an indirect sympathomimetic.
Indirect-acting sympathomimetics, such as pseudoephedrine, other norepinephrine reuptake inhibitors (NRIs), or MAOIs.
Direct-acting sympathomimetics, such as phenylephrine or other α1-adrenergic receptor agonists, including vasopressors such as dobutamine or isoprenaline and β2-adrenergic receptor agonists.
Highly plasma protein-bound drugs: atomoxetine has the potential to displace these drugs from plasma proteins which may potentiate their adverse or toxic effects. In vitro, atomoxetine does not affect the plasma protein binding of aspirin, desipramine, diazepam, paroxetine, phenytoin, or warfarin.
Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.
Pharmacology
Pharmacodynamics
Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, where dopamine transporter (DAT) expression is minimal. In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate, a dopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree. In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.
Atomoxetine’s status as a serotonin transporter (SERT) inhibitor at clinical doses in humans is uncertain. A PET imaging study on rhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively. However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic atomoxetine treatment. Supporting atomoxetine’s selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of the pressor effects of tyramine (a marker of NET inhibition).
Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations. It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site. Atomoxetine’s ability to increase prefrontal cortex firing rate in anaesthetised rats could not be blocked by D1 or α1-adrenergic receptor antagonists, but could be potentiated by NMDA or an α2-adrenergic receptor antagonist, suggesting a glutaminergic mechanism. In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels. Aberrant glutamate and NMDA receptor function have been implicated in the aetiology of ADHD.
Atomoxetine also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner. Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors. Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolisers. It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.
4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects.
Pharmacokinetics
Orally administered atomoxetine is rapidly and completely absorbed. First-pass metabolism by the liver is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolisers and 94% for poor metabolisers. Maximum plasma concentration is reached in 1–2 hours. If taken with food, the maximum plasma concentration decreases by 10–40% and delays the tmax by 3 hours. Drugs affecting gastric pH have no effect on oral bioavailability.
Following intravenous delivery, atomoxetine has a volume of distribution of 0.85 L/kg (indicating distribution primarily in total body water), with limited partitioning into red blood cells. It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%). Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.
The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours. As atomoxetine is metabolised by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolisers. Among CYP2D6 extensive metabolisers, the half-life of atomoxetine averaged 5.34 hours and the half-life of the active metabolite N-desmethylatomoxetine was 8.9 hours. By contrast, among CYP2D6 poor metabolisers the half-life of atomoxetine averaged 20.0 hours and the half-life of N-desmethylatomoxetine averaged 33.3 hours. Steady-state levels of atomoxetine are typically achieved at or around day 10 of regular dosing, with trough plasma concentrations (Ctrough) residing around 30–40°ng/mL; however, both the time to steady-state levels and Ctrough are expected to vary based on a patient’s CYP2D6 profile.
Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6 and 17 μmol/L. Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1.0% and 5% that of atomoxetine in CYP2D6 extensive metabolisers, and are 5% and 45% that of atomoxetine in CYP2D6 poor metabolizers.
Atomoxetine is excreted unchanged in urine at <3% in both extensive and poor CYP2D6 metabolisers, with >96% and 80% of a total dose being excreted in urine, respectively. The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolisers, but only 40% in poor metabolisers. CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.
Pharmacogenomics
Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolisers.
Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolisers.
Chemistry
Atomoxetine, or (−)-methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropylamine, is a white, granular powder that is highly soluble in water.
Detection in Biological Fluids
Atomoxetine may be quantitated in plasma, serum, or whole blood to distinguish extensive versus poor metabolisers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage.
Society and Culture
The drug was originally known as tomoxetine. It was renamed to avoid medication errors, as the name may be confused with tamoxifen.
Brand Names
In India, atomoxetine is sold under brand names including Axetra, Axepta, Attera, Tomoxetin, and Attentin. In Australia, Canada, Italy, Portugal, Romania, Spain, Switzerland, and the US, atomoxetine is sold under the brand name Strattera. In France, hospitals dispense atomoxetine under the brand name Strattera (it is not marketed in France). In the Czech Republic, it is sold under brand names including Mylan. In Poland, it is sold under the brand name Auroxetyn. In Iran, atomoxetine is sold under brand names including Stramox. In Brazil, it is sold under the brand name Atentah. In Turkey, it is sold under the brand names Attex, Setinox, and Atominex. In 2017, a generic version was approved in the United States.
Research
There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD.
Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well studied. Some benefit has also been seen in people with ADHD and autism. As with other norepinephrine reuptake inhibitors it appears to reduce anxiety and depression symptoms, although attention has focused mainly on specific patient groups such as those with concurrent ADHD or methamphetamine dependence.
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Quipazine, also known as 1-(2-quinolinyl)piperazine, is a serotonergic drug of the arylpiperazine family and an analogue of 1-(2-pyridinyl)piperazine which is used in scientific research.
It was first described in the 1960s and was originally intended as an antidepressant but was never developed or marketed for medical use.
Pharmacology
Pharmacodynamics
Quipazine is a serotonin5-HT3 receptor agonist and to a lesser extent a serotonin 5-HT2A receptor agonist, ligand of the serotonin 5-HT2B and 5-HT2C receptors, and serotonin reuptake inhibitor. Activation of the serotonin 5-HT3 is implicated in inducing nausea and vomiting as well as anxiety, which has limited the potential clinical usefulness of quipazine.
Quipazine produces a head-twitch response and other psychedelic-consistent effects in animal studies including in mice, rats, and monkeys. These effects appear to be mediated by activation of the serotonin 5-HT2A receptor, as they are blocked by serotonin 5-HT2A receptor antagonists like ketanserin. The head twitches induced by quipazine are potentiated by the monoamine oxidase inhibitor (MAOI) pargyline. Based on this, it has been suggested that quipazine may act as a serotonin releasing agent and that it may induce the head twitch response by a dual action of serotonin 5-HT2A receptor agonism and induction of serotonin release.
Quipazine did not produce psychedelic effects in humans up to a dose of 25 mg, which was the highest dose tested due to serotonin 5-HT3 receptor-mediated side effects of nausea and gastrointestinal discomfort. Alexander Shulgin has anecdotally claimed that a fully effective psychedelic dose could be reached by blocking serotonin 5-HT3 receptors using the serotonin 5-HT3 receptor antagonist ondansetron.
Quipazine can produce tachycardia, including positive chronotropic and positive inotropic effects, through activation of the serotonin 5-HT3 receptor.
Although quipazine does not generalise to dextroamphetamine in drug discrimination tests of dextroamphetamine-trained rodents, dextroamphetamine and cathinone have been found to partially generalise to quipazine in assays of quipazine-trained rodents. In relation to this, it has been suggested that quipazine might possess some dopaminergic activity, as the discriminative stimulus properties of amphetamine appear to be mediated by dopamine signalling. Relatedly, quipazine has been said to act as a dopamine receptor agonist in addition to serotonin receptor agonist. Conversely however, the generalisation may be due to serotonergic activities of amphetamine and cathinone. Fenfluramine has been found to fully generalise to quipazine, but levofenfluramine, in contrast to quipazine, did not generalise to dextroamphetamine.
Chemistry
Quipazine is a substituted piperazine and quinoline.
It is structurally related to 6-nitroquipazine and 1-(1-naphthyl)piperazine.
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1-(2-Diphenyl)piperazine, also known as RA-7 or Diphenylpiperazine, is a drug which acts as a potent and selective antagonist at the 5-HT7serotonin receptor.
It was discovered as an active metabolite of the synthetic 5-HT7 agonists LP-12 and LP-211, and unexpectedly turned out to be a potent antagonist with selectivity approaching that of the parent molecules, despite its much simpler structure.
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1-(1-Naphthyl)piperazine (1-NP) is a drug which is a phenylpiperazine derivative.
It acts as a non-selective, mixed serotonergic agent, exerting partial agonism at the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptors, while antagonising the 5-HT2A, 5-HT2B, and 5-HT2C receptors. It has also been shown to possess high affinity for the 5-HT3, 5-HT5A, 5-HT6, and 5-HT7 receptors, and may bind to 5-HT4 and the SERT as well. In animals it produces effects including hyperphagia, hyperactivity, and anxiolysis, of which are all likely mediated predominantly or fully by blockade of the 5-HT2C receptor.
Fluprazine (DU-27,716) is a drug of the phenylpiperazine class.
It is a so-called serenic or antiaggressive agent.
It is closely related to several other piperazines, including eltoprazine and batoprazine, and TFMPP, as well as more distantly to the azapirones such as buspirone.
The pharmacology of fluprazine is unknown, but it is likely to act as an agonist at the 5-HT1A and 5-HT1B receptors like its sister compound eltoprazine.
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