Ecopipam (development codes SCH-39166, EBS-101, and PSYRX-101) is a

dopamine antagonist 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 ...

which is under development for the treatment of Lesch-Nyhan syndrome,

Tourette's syndrome Tourette syndrome or Tourette's syndrome (abbreviated as TS or Tourette's) is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) ...

speech disorder Speech disorders or speech impairments are a type of communication disorder in which normal speech is disrupted. This can mean stuttering, lisps, etc. Someone who is unable to speak due to a speech disorder is considered mute. Speech skills ...

s, and

restless legs syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...

. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. Ecopipam acts as a selective dopamine D₁ and D₅

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

antagonist. It is orally active, has an

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of 10hours, crosses the blood–brain barrier, and substantially occupies brain dopamine receptors.

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of ecopipam may include depression,

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, fatigue, sedation,

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

, headaches,

muscle twitching A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more serio ...

, and suicidal ideation, among others. It appears to lack the typical extrapyramidal effects like

tardive dyskinesia Tardive dyskinesia (TD) is a disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips. Additionally, there may be rapid jerking movements or slow writhing movemen ...

that occur with D₂ receptor antagonists. Ecopipam is an

experimental drug An experimental drug is a medicinal product (a drug or vaccine) that has not yet received approval from governmental regulatory authorities for routine use in human or veterinary medicine. A medicinal product may be approved for use in one diseas ...

and has not been approved for medical use. 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. The drug was also under development for the treatment of cocaine-related disorders,

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

, and

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...

, but development for these indications was discontinued.

Pharmacology

Pharmacodynamics

Ecopipam is a selective dopamine D₁ and D₅

antagonist. It shows little

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

for either dopamine D₂-like or 5-HT₂ receptors.

Clinical trials

Based on its profile in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s, ecopipam was first studied as a treatment for

but showed no efficacy.

s including sedation, restlessness,

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

, and

were generally rated mild. There were no reports of

Parkinsonian Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy b ...

-like

extrapyramidal symptoms Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side ...

typically seen with D₂ antagonists. Human clinical studies also showed that ecopipam was an effective antagonist of the acute

euphoric Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

effects of

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

. However, the effect did not persist following repeated administration. Researchers have postulated that dopamine via D₁ receptors in the mesolimbic system is involved with rewarded behaviors and pleasure. One such behavior is

eating Eating (also known as consuming) is the ingestion of food, typically to provide a heterotrophic organism with energy and to allow for growth. Animals and other heterotrophs must eat in order to survive — carnivores eat other animals, he ...

, and ecopipam has been shown in a large clinical study to be an effective treatment for

. However, reports of mild-to-moderate, reversible anxiety and depression made it unsuitable for commercialization as an

anti-obesity drug Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control weight. These medications alter one of the fundamental processes of the human body, weight regulation, by altering either appetite, or absorp ...

, and its development was stopped for that indication. As of 2021, Emalex Biosciences is investigating its potential use for central nervous system disorders. Open-label studies have found ecopipam to reduce

gambling Gambling (also known as betting or gaming) is the wagering of something of value ("the stakes") on a random event with the intent of winning something else of value, where instances of strategy are discounted. Gambling thus requires three el ...

behaviors in subjects with pathological gambling and to decrease the motor and vocal tics in adults with

Tourette syndrome Tourette syndrome or Tourette's syndrome (abbreviated as TS or Tourette's) is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) ...

. A subsequent

double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

placebo-controlled study Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed ...

in pediatric subjects confirmed ecopipam's ability to ameliorate the motor and vocal symptoms seen in patients with Tourette's syndrome. Ecopipam is currently in a phase 2/ 3

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

for the treatment of Tourette's syndrome in children ages 7 to 17. Ecopipam is additionally under development for the treatment of

Lesch–Nyhan syndrome Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the ''HPRT1'' gene located on the X chromosome. LNS ...

(phase 3) and

(phase 1/2). 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). There are currently no U.S. Food and Drug Administration approved medications for the treatment of stuttering.

Chemistry

Chemically, ecopipam is a synthetic

benzazepine Benzazepines are heterocyclic chemical compounds consisting of a benzene ring fused to an azepine ring. Examples include: File:Benazepril structure.svg, Benazepril File:Fenoldopam.svg, Fenoldopam File:GSK-189,254.svg, GSK-189,254 File:Ivabradine ...

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

. It can be synthesized from a simple

tetralin Tetralin (1,2,3,4-tetrahydronaphthalene) is a hydrocarbon having the chemical formula C10H12. It is a partially hydrogenated derivative of naphthalene. It is a colorless liquid that is used as a hydrogen-donor solvent. Production Tetralin is pro ...

derivative: : Ecopipam scheme

References

{{Xenobiotic-sensing receptor modulators 1-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines Chloroarenes Dopamine antagonists Phenols