Chemistry:Ecopipam

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Short description: Chemical compound
Ecopipam
Ecopipam.svg
Ecopipam-3D-balls.png
Clinical data
Other namesEBS-101; PSYRX-101; SCH-39166
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
Chemical and physical data
FormulaC19H20ClNO
Molar mass313.83 g·mol−1
3D model (JSmol)
  (verify)

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]

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]

Clinical trials

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]

Chemistry

Chemically, ecopipam is a synthetic benzazepine derivative. It can be synthesized from a simple tetralin derivative:[20]

Ecopipam scheme.png

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "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 "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. ↑ "Dopamine signaling in reward-related behaviors". Frontiers in Neural Circuits 7: 152. October 11, 2013. doi:10.3389/fncir.2013.00152. PMID 24130517. 
  12. ↑ "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. 
  13. ↑ "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. 
  14. ↑ "Research & Development". Emalex Biosciences. https://emalexbiosciences.com/research-development/#drug-pipeline%20. 
  15. ↑ "A single-blind study of 'as-needed' ecopipam for gambling disorder". Annals of Clinical Psychiatry 26 (3): 179–186. August 2014. PMID 25166480. 
  16. ↑ "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. 
  17. ↑ "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. 
  18. ↑ 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
  19. ↑ 19.0 19.1 "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/. 
  20. ↑ "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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