Ecopipam

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 444234555

| IUPAC_name = (–)-trans-6,7,7a,8,9,13b-Hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naptho-(2,1-b)azepine

| image = Ecopipam.svg

| width =

| image2 = Ecopipam-3D-balls.png

| width2 =

| tradename =

| legal_status = Investigational

| routes_of_administration = By mouth

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life = 10 hours

| excretion =

| IUPHAR_ligand = 3304

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 112108-01-7

| ATC_prefix = none

| ATC_suffix =

| ATC_supplemental =

| PubChem = 107930

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank =

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 0X748O646K

| ChemSpiderID = 97053

| synonyms = EBS-101; PSYRX-101; SCH-39166

| C = 19

| H = 20

| Cl = 1

| N = 1

| O = 1

| SMILES = CN1CCc2cc(c(cc2[C@@H]3[C@@H]1CCc4c3cccc4)O)Cl

| StdInChI = 1S/C19H20ClNO/c1-21-9-8-13-10-16(20)18(22)11-15(13)19-14-5-3-2-4-12(14)6-7-17(19)21/h2-5,10-11,17,19,22H,6-9H2,1H3/t17-,19+/m0/s1

| StdInChIKey = DMJWENQHWZZWDF-PKOBYXMFSA-N

}}

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 syndrome, speech disorders, and restless legs syndrome.{{Cite web |title=Ecopipam - Emalex Biosciences |url=https://adisinsight.springer.com/drugs/800000645 |work=AdisInsight |publisher=Springer Nature Switzerland AG}} It is taken by mouth.{{cite journal | vauthors = Khasnavis T, Torres RJ, Sommerfeld B, Puig JG, Chipkin R, Jinnah HA | title = A double-blind, placebo-controlled, crossover trial of the selective dopamine D1 receptor antagonist ecopipam in patients with Lesch-Nyhan disease | journal = Molecular Genetics and Metabolism | volume = 118 | issue = 3 | pages = 160–166 | date = July 2016 | pmid = 27179999 | doi = 10.1016/j.ymgme.2016.04.012 }}

Ecopipam acts as a selective dopamine D₁ and D₅ receptor antagonist. It is orally active, has an elimination half-life of 10{{nbsp}}hours, crosses the blood–brain barrier, and substantially occupies brain dopamine receptors.{{cite journal | vauthors = Karlsson P, Sedvall G, Halldin C, Swahn CG, Farde L | title = Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man | journal = Psychopharmacology | volume = 121 | issue = 3 | pages = 300–308 | date = October 1995 | pmid = 8584610 | doi = 10.1007/BF02246067 | s2cid = 12659381 }} Side effects of ecopipam may include depression, anxiety, fatigue, sedation, somnolence, insomnia, headaches, muscle twitching, and suicidal ideation, among others.{{cite journal | vauthors = Nathan PJ, O'Neill BV, Napolitano A, Bullmore ET | title = Neuropsychiatric adverse effects of centrally acting antiobesity drugs | journal = CNS Neuroscience & Therapeutics | volume = 17 | issue = 5 | pages = 490–505 | date = October 2011 | pmid = 21951371 | pmc = 6493804 | doi = 10.1111/j.1755-5949.2010.00172.x | quote = 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. }}{{cite journal | vauthors = Gilbert DL, Budman CL, Singer HS, Kurlan R, Chipkin RE | title = A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome | journal = Clinical Neuropharmacology | volume = 37 | issue = 1 | pages = 26–30 | date = 2014 | pmid = 24434529 | doi = 10.1097/WNF.0000000000000017 | s2cid = 24829565 }} It appears to lack the typical extrapyramidal effects like tardive dyskinesia that occur with D₂ receptor antagonists.

Ecopipam is an experimental drug and has not been approved for medical use. It was discovered in the CNS preclinical labs at Schering-Plough Corporation (now Merck) under the direction of Richard Chipkin, PhD. As of April 2024, it is in Phase 3 trials for Tourette Syndrome, Phase 2 trials for Tourette 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, and schizophrenia, but development for these indications was discontinued.

Pharmacology

=Pharmacodynamics=

Ecopipam is a selective dopamine D₁ and D₅ receptor antagonist.{{cite journal | vauthors = Chipkin RE, Iorio LC, Coffin VL, McQuade RD, Berger JG, Barnett A | title = Pharmacological profile of SCH39166: a dopamine D1 selective benzonaphthazepine with potential antipsychotic activity | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 247 | issue = 3 | pages = 1093–1102 | date = December 1988 | pmid = 2905002 }} It shows little affinity for either dopamine D₂-like or 5-HT₂ receptors.

Clinical trials

Based on its profile in animal models, ecopipam was first studied as a treatment for schizophrenia but showed no efficacy.{{cite journal | vauthors = Karlsson P, Smith L, Farde L, Härnryd C, Sedvall G, Wiesel FA | title = Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients | journal = Psychopharmacology | volume = 121 | issue = 3 | pages = 309–316 | date = October 1995 | pmid = 8584611 | doi = 10.1007/bf02246068 | s2cid = 23909094 }}{{cite journal | vauthors = Den Boer JA, van Megen HJ, Fleischhacker WW, Louwerens JW, Slaap BR, Westenberg HG, Burrows GD, Srivastava ON | display-authors = 6 | title = Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia | journal = Psychopharmacology | volume = 121 | issue = 3 | pages = 317–322 | date = October 1995 | pmid = 8584612 | doi = 10.1007/bf02246069 | s2cid = 21837432 }} 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.{{cite journal | vauthors = Haney M, Ward AS, Foltin RW, Fischman MW | title = Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans | journal = Psychopharmacology | volume = 155 | issue = 4 | pages = 330–337 | date = June 2001 | pmid = 11441422 | doi = 10.1007/s002130100725 | s2cid = 973041 }} However, the effect did not persist following repeated administration.{{cite journal | vauthors = Nann-Vernotica E, Donny EC, Bigelow GE, Walsh SL | title = Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine | journal = Psychopharmacology | volume = 155 | issue = 4 | pages = 338–347 | date = June 2001 | pmid = 11441423 | doi = 10.1007/s002130100724 | s2cid = 854984 }}

Researchers have postulated that dopamine via D₁ receptors in the mesolimbic system is involved with rewarded behaviors and pleasure.{{cite journal | vauthors = Baik JH | title = Dopamine signaling in reward-related behaviors | journal = Frontiers in Neural Circuits | volume = 7 | pages = 152 | date = October 11, 2013 | pmid = 24130517 | pmc = 3795306 | doi = 10.3389/fncir.2013.00152 | doi-access = free }} One such behavior is eating, and ecopipam has been shown in a large clinical study to be an effective treatment for obesity.{{cite journal | vauthors = Astrup A, Greenway FL, Ling W, Pedicone L, Lachowicz J, Strader CD, Kwan R | title = Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects | journal = Obesity | volume = 15 | issue = 7 | pages = 1717–1731 | date = July 2007 | pmid = 17636090 | doi = 10.1038/oby.2007.205 | s2cid = 11657547 | doi-access = free }} 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.{{cite journal | vauthors = Coulter AA, Rebello CJ, Greenway FL | title = Centrally Acting Agents for Obesity: Past, Present, and Future | journal = Drugs | volume = 78 | issue = 11 | pages = 1113–1132 | date = July 2018 | pmid = 30014268 | pmc = 6095132 | doi = 10.1007/s40265-018-0946-y }}

As of 2021, Emalex Biosciences is investigating its potential use for central nervous system disorders.{{cite web | url = https://emalexbiosciences.com/research-development/#drug-pipeline%20 | title = Research & Development | publisher = Emalex Biosciences }} Open-label studies have found ecopipam to reduce gambling behaviors in subjects with pathological gambling{{cite journal | vauthors = Grant JE, Odlaug BL, Black DW, Fong T, Davtian M, Chipkin R, Kim SW | title = A single-blind study of 'as-needed' ecopipam for gambling disorder | journal = Annals of Clinical Psychiatry | volume = 26 | issue = 3 | pages = 179–186 | date = August 2014 | pmid = 25166480 }} and to decrease the motor and vocal tics in adults with Tourette syndrome.{{cite journal | vauthors = Gilbert DL, Budman CL, Singer HS, Kurlan R, Chipkin RE | title = A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome | journal = Clinical Neuropharmacology | volume = 37 | issue = 1 | pages = 26–30 | date = January–February 2014 | pmid = 24434529 | doi = 10.1097/WNF.0000000000000017 | s2cid = 24829565 }} 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 syndrome.{{cite journal | vauthors = Gilbert DL, Murphy TK, Jankovic J, Budman CL, Black KJ, Kurlan RM, Coffman KA, McCracken JT, Juncos J, Grant JE, Chipkin RE | display-authors = 6 | title = Ecopipam, a D1 receptor antagonist, for treatment of tourette syndrome in children: A randomized, placebo-controlled crossover study | journal = Movement Disorders | volume = 33 | issue = 8 | pages = 1272–1280 | date = August 2018 | pmid = 30192018 | doi = 10.1002/mds.27457 | s2cid = 52169188 }} Ecopipam is currently in a Phase 3 clinical trial for the treatment of Tourette syndrome in children ages 7 to 17{{ClinicalTrialsGov|NCT04007991|Multicenter, Placebo-Controlled, Double-Blind, Randomized, Parallel-Group, Phase 2b Study to Evaluate the Efficacy and Safety of Ecopipam in Children and Adolescents With Tourette's Syndrome}} and for the treatment of restless syndrome augmentation (Phase 1/2)

Ecopipam is an investigational first-in-class drug also being evaluated for the treatment of childhood-onset fluency disorder (stuttering) in adults.{{Cite web |url=https://emalexbiosciences.com/news/first-patient-dosed-in-emalex-biosciences-phase-2-clinical-trial-for-stuttering/ |title=First Patient Dosed in Emalex Biosciences Phase 2 Clinical Trial for Stuttering |work=Emalex Biosciences |date=15 December 2020}} There are currently no U.S. Food and Drug Administration (FDA) approved medications for this disorder.

Chemistry

Chemically, ecopipam is a synthetic benzazepine derivative. It can be synthesized from a simple tetralin derivative:{{cite journal | vauthors = Hou D, Schumacher D | title = The selection of a commercial route for the D1 antagonist Sch-39166 | journal = Current Opinion in Drug Discovery & Development | volume = 4 | issue = 6 | pages = 792–799 | date = November 2001 | pmid = 11899619 }}

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References

Category:1-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines

Category:Chloroarenes

Category:D1 antagonists

Category:Dopamine antagonists

Category:Experimental drugs

Category:Hydroxyarenes