Ecopipam

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
Clinical data
Other namesEBS-101; PSYRX-101; SCH-39166
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
IUPAC name
  • (–)-trans-6,7,7a,8,9,13b-Hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naptho-(2,1-b)azepine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H20ClNO
Molar mass313.83 g·mol−1
3D model (JSmol)
SMILES
  • CN1CCc2cc(c(cc2[C@@H]3[C@@H]1CCc4c3cccc4)O)Cl
InChI
  • InChI=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
  • Key:DMJWENQHWZZWDF-PKOBYXMFSA-N
  (verify)

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]

References
  1. "Ecopipam - Emalex Biosciences - AdisInsight".
  2. Khasnavis T, Torres RJ, Sommerfeld B, Puig JG, Chipkin R, Jinnah HA (July 2016). "A double-blind, placebo-controlled, crossover trial of the selective dopamine D1 receptor antagonist ecopipam in patients with Lesch-Nyhan disease". Mol Genet Metab. 118 (3): 160–166. doi:10.1016/j.ymgme.2016.04.012. PMID 27179999.
  3. Karlsson P, Sedvall G, Halldin C, Swahn CG, Farde L (October 1995). "Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man". Psychopharmacology (Berl). 121 (3): 300–8. doi:10.1007/BF02246067. PMID 8584610. S2CID 12659381.
  4. Nathan PJ, O'Neill BV, Napolitano A, Bullmore ET (October 2011). "Neuropsychiatric adverse effects of centrally acting antiobesity drugs". CNS Neurosci Ther. 17 (5): 490–505. doi:10.1111/j.1755-5949.2010.00172.x. PMC 6493804. 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. Gilbert DL, Budman CL, Singer HS, Kurlan R, Chipkin RE (2014). "A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome". Clin Neuropharmacol. 37 (1): 26–30. doi:10.1097/WNF.0000000000000017. PMID 24434529. S2CID 24829565.
  6. Chipkin RE, Iorio LC, Coffin VL, McQuade RD, Berger JG, Barnett A (December 1988). "Pharmacological profile of SCH39166: a dopamine D1 selective benzonaphthazepine with potential antipsychotic activity". The Journal of Pharmacology and Experimental Therapeutics. 247 (3): 1093–102. PMID 2905002.
  7. Karlsson P, Smith L, Farde L, Härnryd C, Sedvall G, Wiesel FA (October 1995). "Lack of apparent antipsychotic effect of the D1-dopamine receptor antagonist SCH39166 in acutely ill schizophrenic patients". Psychopharmacology. 121 (3): 309–16. doi:10.1007/bf02246068. PMID 8584611. S2CID 23909094.
  8. Den Boer JA, van Megen HJ, Fleischhacker WW, Louwerens JW, Slaap BR, Westenberg HG, Burrows GD, Srivastava ON (October 1995). "Differential effects of the D1-DA receptor antagonist SCH39166 on positive and negative symptoms of schizophrenia". Psychopharmacology. 121 (3): 317–22. doi:10.1007/bf02246069. PMID 8584612. S2CID 21837432.
  9. Haney M, Ward AS, Foltin RW, Fischman MW (June 2001). "Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans". Psychopharmacology. 155 (4): 330–7. doi:10.1007/s002130100725. PMID 11441422. S2CID 973041.
  10. Nann-Vernotica E, Donny EC, Bigelow GE, Walsh SL (June 2001). "Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine". Psychopharmacology. 155 (4): 338–47. doi:10.1007/s002130100724. PMID 11441423. S2CID 854984.
  11. Baik JH (October 11, 2013). "Dopamine signaling in reward-related behaviors". Front Neural Circuits. 7: 152. doi:10.3389/fncir.2013.00152. PMC 3795306. PMID 24130517.
  12. Astrup A, Greenway FL, Ling W, Pedicone L, Lachowicz J, Strader CD, Kwan R, Ecopipam Obesity Study Group (2007). "Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects". Obesity. 15 (7): 1717–31. doi:10.1038/oby.2007.205. PMID 17636090. S2CID 11657547.
  13. Coulter, Ann A.; Rebello, Candida J.; Greenway, Frank L. (2018). "Centrally Acting Agents for Obesity: Past, Present, and Future". Drugs. 78 (11): 1113–1132. doi:10.1007/s40265-018-0946-y. PMC 6095132. PMID 30014268.
  14. "Research & Development". Emalex Biosciences.
  15. Grant JE, Odlaug BL, Black DW, Fong T, Davtian M, Chipkin R, Kim SW (August 2014). "A single-blind study of 'as-needed' ecopipam for gambling disorder". Ann Clin Psychiatry. 26 (3): 179–86. PMID 25166480.
  16. Gilbert DL, Budman CL, Singer HS, Kurlan R, Chipkin RE (January–February 2014). "A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome". Clin Neuropharmacol. 37 (1): 26–30. doi:10.1097/WNF.0000000000000017. PMID 24434529. S2CID 24829565.
  17. Gilbert, Donald L.; Murphy, Tanya K.; Jankovic, Joseph; Budman, Cathy L.; Black, Kevin J.; Kurlan, Roger M.; Coffman, Keith A.; McCracken, James T.; Juncos, Jorge; Grant, Jon E.; Chipkin, Richard E. (2018). "Ecopipam, a D1 receptor antagonist, for treatment of tourette syndrome in children: A randomized, placebo-controlled crossover study". Movement Disorders. 33 (8): 1272–1280. doi:10.1002/mds.27457. PMID 30192018. S2CID 52169188.
  18. "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". March 8, 2021 – via clinicaltrials.gov. {{cite journal}}: Cite journal requires |journal= (help)
  19. "First Patient Dosed in Emalex Biosciences Phase 2 Clinical Trial for Stuttering - Emalex Biosciences".
  20. Hou, D; Schumacher, D (2001). "The selection of a commercial route for the D1 antagonist Sch-39166". Current Opinion in Drug Discovery & Development. 4 (6): 792–9. PMID 11899619.


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