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Other names | EBS-101; PSYRX-101; SCH-39166 |
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Formula | C19H20ClNO |
Molar mass | 313.83 g·mol−1 |
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Ecopipam (development codes SCH-39166, EBS-101, and PSYRX-101) is a dopamine antagonist which is under development for the treatment of Lesch-Nyhan syndrome, Tourette's syndrome, speech disorders, and restless legs syndrome. [1] It is taken by mouth. [2]
Ecopipam acts as a selective dopamine D1 and D5 receptor antagonist. [1] It is orally active, has an elimination half-life of 10 hours, crosses the blood–brain barrier, and substantially occupies brain dopamine receptors. [2] [3] Side effects of ecopipam may include depression, anxiety, fatigue, sedation, somnolence, insomnia, headaches, muscle twitching, and suicidal ideation, among others. [4] [5] [2] It appears to lack the typical extrapyramidal effects like tardive dyskinesia that occur with D2 receptor antagonists. [2]
Ecopipam is an experimental drug and has not been approved for medical use. [1] As of April 2022, it is in phase 3 trials for Lesch-Nyhan syndrome, phase 2 trials for Tourette's syndrome and speech disorders, and phase 2/phase 1 trials for restless legs syndrome. [1] The drug was also under development for the treatment of cocaine-related disorders, obesity, and schizophrenia, but development for these indications was discontinued. [1]
Ecopipam is a selective dopamine D1 and D5 receptor antagonist. [6] It shows little affinity for either dopamine D2-like or 5-HT2 receptors. [6]
Based on its profile in animal models, ecopipam was first studied as a treatment for schizophrenia but showed no efficacy. [7] [8] Side effects including sedation, restlessness, vomiting, and anxiety were generally rated mild. There were no reports of Parkinsonian-like extrapyramidal symptoms typically seen with D2 antagonists.
Human clinical studies also showed that ecopipam was an effective antagonist of the acute euphoric effects of cocaine. [9] However, the effect did not persist following repeated administration. [10]
Researchers have postulated that dopamine via D1 receptors in the mesolimbic system is involved with rewarded behaviors and pleasure. [11] One such behavior is eating, and ecopipam has been shown in a large clinical study to be an effective treatment for obesity. [12] However, reports of mild-to-moderate, reversible anxiety and depression made it unsuitable for commercialization as an anti-obesity drug, and its development was stopped for that indication. [13]
As of 2021, Emalex Biosciences is investigating its potential use for central nervous system disorders. [14] Open-label studies have found ecopipam to reduce gambling behaviors in subjects with pathological gambling [15] and to decrease the motor and vocal tics in adults with Tourette syndrome. [16] A subsequent double-blind placebo-controlled study in pediatric subjects confirmed ecopipam's ability to ameliorate the motor and vocal symptoms seen in patients with Tourette's syndrome. [17] Ecopipam is currently in a phase 2/3 clinical trial for the treatment of Tourette's syndrome in children ages 7 to 17. [18]
Ecopipam is additionally under development for the treatment of Lesch–Nyhan syndrome (phase 3) and restless legs syndrome (phase 1/2). [1]
Ecopipam is an investigational first-in-class drug being evaluated for the treatment of childhood-onset fluency disorder (stuttering) in adults. It is under development for the treatment of stuttering (phase 2). [19] There are currently no U.S. Food and Drug Administration approved medications for the treatment of stuttering. [19]
Chemically, ecopipam is a synthetic benzazepine derivative. It can be synthesized from a simple tetralin derivative: [20]
Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis, principally in schizophrenia but also in a range of other psychotic disorders. They are also the mainstay, together with mood stabilizers, in the treatment of bipolar disorder. Moreover, they are also used as adjuncts in the treatment of treatment-resistant major depressive disorder.
Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, severe behavioral problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given orally, by intramuscular injection, or intravenously.
Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.
Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder; other uses include as an add-on treatment in major depressive disorder and obsessive compulsive disorder (OCD), tic disorders, and irritability associated with autism. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.
Coprolalia is involuntary swearing or the involuntary utterance of obscene words or socially inappropriate and derogatory remarks. The word comes from the Greek κόπρος, meaning "dung, feces", and λαλιά "speech", from λαλεῖν "to talk".
A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.
Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold under the brand names Barhemsys and Solian, Socian, Deniban and others. At very low doses it is also used to treat dysthymia.
Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other antidepressants with similar discontinuation rates overall but fewer discontinuations due to side effects. Another review also found it was similarly effective to many other antidepressants.
Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.
A dopamine agonist(DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. The use of dopamine agonists is associated with impulse control disorders and dopamine agonist withdrawal syndrome (DAWS).
Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.
Tiapride is a drug that selectively blocks D2 and D3 dopamine receptors in the brain. It is used to treat a variety of neurological and psychiatric disorders including dyskinesia, alcohol withdrawal syndrome, negative symptoms of psychosis, and agitation and aggression in the elderly. A derivative of benzamide, tiapride is chemically and functionally similar to other benzamide antipsychotics such as sulpiride and amisulpride known for their dopamine antagonist effects.
Piquindone (Ro 22-1319) is an atypical antipsychotic with a tricyclic structure that was developed in the 1980s but was never marketed. It acts as a selective D2 receptor antagonist, though based on its effects profile its selectivity may be considered controversial. Unlike most other D2 receptor ligands, piquindone displays Na+-dependent binding, a property it shares with tropapride, zetidoline, and metoclopramide.
Cariprazine, sold under the brand names Vraylar,Reagila and Symvenu among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth.
Brexpiprazole, sold under the brand name Rexulti among others, is a medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease. It is an atypical antipsychotic.
Brilaroxazine, also known as oxaripiprazole, is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of neuropsychiatric and inflammatory disorders. It has currently completed the first of two phase III clinical trials for schizophrenia. Reviva Pharmaceuticals also intends to investigate brilaroxazine for the treatment of bipolar disorder, major depressive disorder, attention deficit hyperactivity disorder (ADD/ADHD), psychosis/agitation associated with Alzheimer's disease, Parkinson's disease psychosis, as well as the inflammatory disorders pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and psoriasis. The FDA granted brilaroxazine orphan drug designation for the treatment of PAH and IPF.
Valbenazine, sold under the brand name Ingrezza, is a medication used to treat tardive dyskinesia. It acts as a vesicular monoamine transporter 2 (VMAT2) inhibitor.
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.
The dopamine hypothesis of stuttering attributes to the phenomenon of stuttering a hyperactive and disturbed dopaminergic signal transduction in the brain. The theory is derived from observations in medical neuroimaging and from the empirical response of some antipsychotics and their antagonistic effects on the dopamine receptor. However, it is important to outline that the hypothesis does not consider the excessive dopaminergic activity as the direct cause of stuttering; instead, this synaptic dysregulation is a symptom of a greater disorder that affects other brain pathways and structures.
Mevidalen (developmental code name LY-3154207) is a dopaminergic drug which is under development for the treatment of Lewy body disease, including those with Parkinson's disease. It acts as a selective positive allosteric modulator (PAM) of the dopamine D1 receptor. The drug is orally active and crosses the blood–brain barrier. It is a tetrahydroisoquinoline and is a close analogue of DETQ, another D1 receptor PAM. Mevidalen has been found to have wakefulness-promoting effects in sleep-deprived humans. Side effects of mevidalen have been reported to include increased heart rate and blood pressure, insomnia, dizziness, nausea, vomiting, anxiety, nervousness, fatigue, headaches, palpitations, and contact dermatitis, as well as falls in those with dementia. As of March 2022, mevidalen is in phase 2 clinical trials for the treatment of Lewy body disease. Besides for movement disorders and dementia, D1 receptor PAMs like mevidalen might have value in the treatment of certain neuropsychiatric disorders, such as depression, excessive somnolence, and attention deficit hyperactivity disorder.
Recently a study reported findings from human phase 2 and phase 3 clinical trials examining the potential of the D1/D5 receptor antagonist, ecopipam, to enhance and maintain weight loss in obese patients [61]. While these studies showed promising weight loss in both phase 2 and phase 3, there were unexpected treatment related neuropsychiatric adverse events (ecopipam 31% vs. placebo 15%) in the phase 3 clinical trials (that were not observed in the phase 2 studies) and as a consequence phase 3 studies were discontinued. The neuropsychiatric adverse events included depression (ecopipam 16% vs. placebo 6%), anxiety (ecopipam 15% vs. placebo 6%), suicidal ideation (ecopipam 2% vs. placebo 1%), insomnia (ecopipam 17% vs. placebo 7%), fatigue (ecopipam 15% vs. placebo 6%), and somnolence (ecopipam 15% vs. placebo 4%). Psychiatric adverse events also accounted for more than half of the discontinuations because of treatment related adverse effects in the ecopipam group.