Ecopipam

{{Short description|Investigational dopamine antagonist}} {{Infobox drug | Watchedfields = changed | verifiedrevid = 444234555 | IUPAC_name = (–)-''trans''-6,7,7a,8,9,13b-Hexahydro-3-chloro-2-hydroxy-''N''-methyl-5''H''-benzo[d]naptho-(2,1-b)azepine | image = Ecopipam.svg | image_class = skin-invert-image | width = | image2 = Ecopipam-3D-balls.png | image_class2 = bg-transparent | 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.<ref name="AdisInsight">{{Cite web |title=Ecopipam - Emalex Biosciences |url=https://adisinsight.springer.com/drugs/800000645 |work=AdisInsight |publisher=Springer Nature Switzerland AG}}</ref> It is taken by mouth.<ref name="pmid27179999">{{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 }}</ref>

Ecopipam acts as a selective dopamine D1 and D5 receptor antagonist.<ref name="AdisInsight" /> It is orally active, has an elimination half-life of 10{{nbsp}}hours, crosses the blood–brain barrier, and substantially occupies brain dopamine receptors.<ref name="pmid27179999" /><ref name="pmid8584610">{{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 }}</ref> Side effects of ecopipam may include depression, anxiety, fatigue, sedation, somnolence, insomnia, headaches, muscle twitching, and suicidal ideation, among others.<ref name="pmid21951371">{{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. }}</ref><ref name="pmid24434529">{{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 }}</ref><ref name="pmid27179999" /> It appears to lack the typical extrapyramidal effects like tardive dyskinesia that occur with D2 receptor antagonists.<ref name="pmid27179999" />

Ecopipam is an experimental drug and has not been approved for medical use.<ref name="AdisInsight" /> It was discovered in the CNS preclinical labs at Schering-Plough Corporation (now Merck).<ref name="pmid2905002" /> 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.<ref name="AdisInsight" /> The drug was also under development for the treatment of cocaine-related disorders, obesity, and schizophrenia, but development for these indications was discontinued.<ref name="AdisInsight" />

==Pharmacology==

===Pharmacodynamics=== Ecopipam is a selective dopamine D1 and D5 receptor antagonist.<ref name="pmid2905002">{{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 }}</ref> It shows little affinity for either dopamine D2-like or 5-HT2 receptors.<ref name="pmid2905002" />

==Research== Based on its profile in animal models, ecopipam was first studied as a treatment for schizophrenia but showed no efficacy.<ref name="pmid8584611">{{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 }}</ref><ref name="pmid8584612">{{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 }}</ref> 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.<ref name="pmid11441422">{{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 }}</ref> However, the effect did not persist following repeated administration.<ref name="pmid11441423">{{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 }}</ref> Open-label studies found ecopipam to reduce gambling behaviors in subjects with pathological gambling.<ref name="pmid251664802">{{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 }}</ref>

Researchers have postulated that dopamine via D1 receptors in the mesolimbic system are involved with rewarded behaviors and pleasure.<ref name="pmid24130517">{{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 }}</ref> One such behavior is eating, and ecopipam has been shown in a large clinical study to be an effective treatment for obesity.<ref name="pmid17636090">{{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 }}</ref> 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.<ref>{{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 }}</ref>

Ecopipam was under development for the treatment of Lesch–Nyhan syndrome and restless legs syndrome.<ref name="AdisInsight" /> It was also a first-in-class drug evaluated for the treatment of childhood-onset fluency disorder (stuttering) in adults.<ref name="Emalex">{{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}}</ref> There are currently no U.S. Food and Drug Administration (FDA) approved medications for this disorder.<ref name="Emalex" />

As of 2025, Emalex Biosciences is investigating its potential use for other central nervous system disorders.<ref>{{cite web | url = https://emalexbiosciences.com/research-development/#drug-pipeline%20 | title = Research & Development | publisher = Emalex Biosciences }}</ref> Open-label studies found ecopipam to decrease tic severity in adults with Tourette syndrome.<ref name="pmid244345292">{{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 }}</ref> A subsequent double-blind placebo-controlled study confirmed ecopipam's ability to ameliorate motor and vocal tics in pediatric participants with Tourette syndrome.<ref>{{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 }}</ref> A subsequent parallel-group, randomized, placebo-controlled clinical trial in children ages 7 to 17 with Tourette syndrome <ref>{{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}}</ref> found ecopipam superior to placebo in reducing tic severity;<ref>{{cite journal | vauthors = Gilbert DL, Dubow JS, Cunniff TM, Wanaski SP, Atkinson SD, Mahableshwarkar AR | title = Ecopipam for Tourette syndrome: A randomized trial | journal = Pediatrics | volume = 151 | issue = 2 | pages = e2022059574 | date = February 2023 | pmid = 36628546 | doi = 10.1542/peds.2022-059574}}</ref> response, defined as a 25% or greater improvement on the standard tic severity scale (YGTSS total tic score), occurred in 74% of participants taking ecopipam versus 43% of those on placebo (odds ratio 3.7, 95% CI 1.8 to 7.4), for a number needed to treat of 3.0. Overall ecopipam was well tolerated, without evidence of the motor or metabolic side effects common to D2 receptor antagonists.

Ecopipam is also being studied for the treatment of restless legs syndrome augmentation (phase 1/2).<ref name="AdisInsight" /> A small pilot study supported its potential utility for this use.<ref>{{cite journal | vauthors = Ondo WG, Olubajo T | title = Exploratory cross-over, trial of augmented RLS with the dopamine receptor 1/5 antagonist ecopipam D1/D5 antagonist ecopipam for augmented RLS | journal = International Journal of Neuroscience | volume = 132 | issue = 8 | pages = 778–782 | date = August 2022 | pmid = 33066723 | doi = 10.1080/00207454.2020.1838515}}</ref>

==Chemistry== Chemically, ecopipam is a synthetic benzazepine derivative. It can be synthesized from a simple tetralin derivative:<ref>{{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 }}</ref>

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==See also== * List of investigational Tourette's syndrome drugs * Berupipam (NNC 22–0010) * NNC 01-0687 (ADX-10061) * Odapipam (NNC 01–0756) * SCH-23390

== References == {{Reflist}}

Category:1-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines Category:Chloroarenes Category:D1 antagonists Category:Dopamine antagonists Category:Experimental drugs Category:Hydroxyarenes