Chemistry:Ecopipam

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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 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] It was discovered in the CNS preclinical labs at Schering-Plough Corporation (now Merck).[6] 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.[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]

Pharmacology

Pharmacodynamics

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]

Research

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] Open-label studies found ecopipam to reduce gambling behaviors in subjects with pathological gambling.[11]

Researchers have postulated that dopamine via D1 receptors in the mesolimbic system are involved with rewarded behaviors and pleasure.[12] One such behavior is eating, and ecopipam has been shown in a large clinical study to be an effective treatment for obesity.[13] 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.[14]

Ecopipam was under development for the treatment of Lesch–Nyhan syndrome and restless legs syndrome.[1] It was also a first-in-class drug evaluated for the treatment of childhood-onset fluency disorder (stuttering) in adults.[15] There are currently no U.S. Food and Drug Administration (FDA) approved medications for this disorder.[15]

As of 2025, Emalex Biosciences is investigating its potential use for other central nervous system disorders.[16] Open-label studies found ecopipam to decrease tic severity in adults with Tourette syndrome.[17] A subsequent double-blind placebo-controlled study confirmed ecopipam's ability to ameliorate motor and vocal tics in pediatric participants with Tourette syndrome.[18] A subsequent parallel-group, randomized, placebo-controlled clinical trial in children ages 7 to 17 with Tourette syndrome [19] found ecopipam superior to placebo in reducing tic severity;[20] 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)[1]. A small pilot study supported its potential utility for this use.[21]

Chemistry

Chemically, ecopipam is a synthetic benzazepine derivative. It can be synthesized from a simple tetralin derivative:[22]

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See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Ecopipam - Emalex Biosciences". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800000645. 
  2. ↑ 2.0 2.1 2.2 2.3 "A double-blind, placebo-controlled, crossover trial of the selective dopamine D1 receptor antagonist ecopipam in patients with Lesch-Nyhan disease". Molecular Genetics and Metabolism 118 (3): 160–166. July 2016. doi:10.1016/j.ymgme.2016.04.012. PMID 27179999. 
  3. ↑ "Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man". Psychopharmacology 121 (3): 300–308. October 1995. doi:10.1007/BF02246067. PMID 8584610. 
  4. ↑ "Neuropsychiatric adverse effects of centrally acting antiobesity drugs". CNS Neuroscience & Therapeutics 17 (5): 490–505. October 2011. doi:10.1111/j.1755-5949.2010.00172.x. PMID 21951371. "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.". 
  5. ↑ "A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome". Clinical Neuropharmacology 37 (1): 26–30. 2014. doi:10.1097/WNF.0000000000000017. PMID 24434529. 
  6. ↑ 6.0 6.1 6.2 "Pharmacological profile of SCH39166: a dopamine D1 selective benzonaphthazepine with potential antipsychotic activity". The Journal of Pharmacology and Experimental Therapeutics 247 (3): 1093–1102. December 1988. PMID 2905002. 
  7. ↑ "Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients". Psychopharmacology 121 (3): 309–316. October 1995. doi:10.1007/bf02246068. PMID 8584611. 
  8. ↑ "Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia". Psychopharmacology 121 (3): 317–322. October 1995. doi:10.1007/bf02246069. PMID 8584612. 
  9. ↑ "Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans". Psychopharmacology 155 (4): 330–337. June 2001. doi:10.1007/s002130100725. PMID 11441422. 
  10. ↑ "Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine". Psychopharmacology 155 (4): 338–347. June 2001. doi:10.1007/s002130100724. PMID 11441423. 
  11. ↑ "A single-blind study of 'as-needed' ecopipam for gambling disorder". Annals of Clinical Psychiatry 26 (3): 179–186. August 2014. PMID 25166480. 
  12. ↑ "Dopamine signaling in reward-related behaviors". Frontiers in Neural Circuits 7: 152. October 11, 2013. doi:10.3389/fncir.2013.00152. PMID 24130517. 
  13. ↑ "Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects". Obesity 15 (7): 1717–1731. July 2007. doi:10.1038/oby.2007.205. PMID 17636090. 
  14. ↑ "Centrally Acting Agents for Obesity: Past, Present, and Future". Drugs 78 (11): 1113–1132. July 2018. doi:10.1007/s40265-018-0946-y. PMID 30014268. 
  15. ↑ 15.0 15.1 "First Patient Dosed in Emalex Biosciences Phase 2 Clinical Trial for Stuttering". Emalex Biosciences. 15 December 2020. https://emalexbiosciences.com/news/first-patient-dosed-in-emalex-biosciences-phase-2-clinical-trial-for-stuttering/. 
  16. ↑ "Research & Development". Emalex Biosciences. https://emalexbiosciences.com/research-development/#drug-pipeline%20. 
  17. ↑ "A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome". Clinical Neuropharmacology 37 (1): 26–30. January–February 2014. doi:10.1097/WNF.0000000000000017. PMID 24434529. 
  18. ↑ "Ecopipam, a D1 receptor antagonist, for treatment of tourette syndrome in children: A randomized, placebo-controlled crossover study". Movement Disorders 33 (8): 1272–1280. August 2018. doi:10.1002/mds.27457. PMID 30192018. 
  19. ↑ Clinical trial number NCT04007991 for "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" at ClinicalTrials.gov
  20. ↑ "Ecopipam for Tourette syndrome: A randomized trial". Pediatrics 151 (2): e2022059574. February 2023. doi:10.1542/peds.2022-059574. PMID 36628546. 
  21. ↑ "Exploratory cross-over, trial of augmented RLS with the dopamine receptor 1/5 antagonist ecopipam D1/D5 antagonist ecopipam for augmented RLS". International Journal of Neuroscience 132 (8): 778-782. August 2022. doi:10.1080/00207454.2020.1838515. PMID 33066723. 
  22. ↑ "The selection of a commercial route for the D1 antagonist Sch-39166". Current Opinion in Drug Discovery & Development 4 (6): 792–799. November 2001. PMID 11899619. 



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