Ecopipam

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Ecopipam
Clinical data
ATC code
  • none
Identifiers
  • (–)-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)
  • CN1CCc2cc(c(cc2[C@@H]3[C@@H]1CCc4c3cccc4)O)Cl
  • 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 (SCH-39166) is a synthetic benzazepine derivative drug that acts as a selective dopamine D1/D5 receptor antagonist, with little affinity for either dopamine D2-like or 5-HT2 receptors.[1]

Clinical trials

Based on its profile in animal models, ecopipam was first studied as a treatment for schizophrenia but showed no activity.[2][3] Side effects including sedation, restlessness, emesis 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.[4] However, the effect did not persist following repeated administration.[5]

Researchers have postulated that dopamine via D1 receptors in the mesolimbic system is involved with rewarded behaviors and pleasure.[6] One such behavior is eating, and ecopipam has been shown in a large clinical study to be an effective treatment for obesity.[7] 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.

Recent (2014) open label studies have shown ecopipam to reduce gambling behaviors in subjects with pathological gambling[8] and to decrease the motor and vocal tics in adults with Tourette’s Syndrome.[9] 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. (Ecopipam, a D1 Receptor Antagonist, for Treatment of Tourette Syndrome in Children: A Randomized, Placebo-controlled Crossover Study, Gilbert et al., Movement Disorders, Volume33 (8):August 2018, Pages 1272-1280). Ecopipam is currently in a Phase 2/3 clinical trial for the treatment of Tourette's syndrome in children ages 7–17 conducted by the biotechnology company Emalex Bioscineces (who purchased Psyadon Pharmaceuticals in 2018) https://clinicaltrials.gov/ct2/show/NCT04007991?term=ecopipam&cond=Tourette+Syndrome+in+Children&draw=2&rank=1.

Chemical synthesis

Ecopipam can be synthesized from a simple tetralin derivative:[10]

References

  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ 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.
  9. ^ 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.
  10. ^ 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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