Ecopipam: Difference between revisions

{{Short description|Investigational dopamine antagonist}}

{{Drugbox

| 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

| width =

| image2 = Ecopipam-3D-balls.png

| width2 =

<!--Clinical data-->

| tradename =

| legal_status = Investigational

| routes_of_administration =

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| bioavailability =

| protein_bound =

| metabolism =

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<!--Identifiers-->

| IUPHAR_ligand = 3304

| CAS_number_Ref = {{cascite|correct|??}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 0X748O646K

| ChemSpiderID = 97053

| synonyms = EBS-101; PSYRX-101; SCH-39166

<!--Chemical data-->

| 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's syndrome]], [[speech disorder]]s, and [[restless legs syndrome]].<ref name="AdisInsight" /> It is taken [[oral administration|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 [[binding selectivity|selective]] [[dopamine]] [[dopamine receptor D1|D₁]] and [[dopamine receptor D5|D₅]] [[receptor (biochemistry)|receptor]] [[antagonist (pharmacology)|antagonist]].<ref name="AdisInsight" /> It is [[oral administration|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 effect]]s of ecopipam may include [[depression (mood)|depression]], [[anxiety]], [[fatigue (medical)|fatigue]], [[sedation]], [[somnolence]], [[insomnia]], [[headache]]s, [[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 effect]]s like [[tardive dyskinesia]] that occur with [[D2 receptor|D₂ receptor]] antagonists.<ref name="pmid27179999" />

Ecopipam is an [[experimental drug]] and has not been approved for medical use.<ref name="AdisInsight" /> As of April 2022, it is in [[Phases of clinical research#Phase III|phase 3]] trials for Lesch-Nyhan syndrome, [[Phases of clinical research#Phase II|phase 2]] trials for Tourette's syndrome and speech disorders, and phase 2/[[Phases of clinical research#Phase III|phase 1]] trials for restless legs syndrome.<ref name="AdisInsight" /> The drug was also under development for the treatment of [[cocaine dependence|cocaine-related disorder]]s, [[obesity]], and [[schizophrenia]], but development for these indications was discontinued.<ref name="AdisInsight" />

==Pharmacology==

===Pharmacodynamics===

Ecopipam is a [[binding selectivity|selective]] [[dopamine]] [[dopamine receptor D1|D₁]] and [[dopamine receptor D5|D₅]] [[receptor (biochemistry)|receptor]] [[antagonist (pharmacology)|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 (pharmacology)|affinity]] for either dopamine [[D2-like receptor|D₂-like]] or [[5-HT2 receptor|5-HT₂ receptor]]s.<ref name="pmid2905002" />

Based on its profile in [[animal model]]s, 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 effect]]s including [[sedation]], [[psychomotor agitation|restlessness]], [[vomiting]], and [[anxiety]] were generally rated mild. There were no reports of [[Parkinsonian]]-like [[extrapyramidal symptoms]] typically seen with [[D2 receptor antagonist|D₂ antagonist]]s.

Human clinical studies also showed that ecopipam was an effective antagonist of the acute [[euphoria|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>

Researchers have postulated that dopamine via D₁ receptors in the [[mesolimbic system]] is involved with [[reward system|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 (mood)|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>

As of 2021, Emalex Biosciences is investigating its potential use for [[central nervous system disorder]]s.<ref>{{cite web | url = https://emalexbiosciences.com/research-development/#drug-pipeline%20 | title = Research & Development | publisher = Emalex Biosciences }}</ref> [[Open-label study|Open-label studies]] have 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> and to decrease the [[tic|motor and vocal tics]] 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 study|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.<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> Ecopipam is currently in a [[Phases of clinical research#Phase 2|phase 2]]/[[Phases of clinical research#Phase 3|3]] [[clinical trial]] for the treatment of Tourette's syndrome in children ages 7 to 17.<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>

Ecopipam is additionally under development for the treatment of [[Lesch–Nyhan syndrome]] (phase 3) and [[restless legs syndrome]] (phase 1/2).<ref name="AdisInsight">{{Cite web|url=https://adisinsight.springer.com/drugs/800000645|title=Ecopipam - Emalex Biosciences | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref>

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).<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 approved medications for the treatment of stuttering.<ref name="Emalex" />

==Chemistry==

Chemically, ecopipam is a [[synthetic compound|synthetic]] [[benzazepine]] [[chemical derivative|derivative]]. It can be [[chemical synthesis|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>

: [[File:Ecopipam scheme.png|500px]]{{clear left}}

== References ==

{{Reflist}}

{{Dopamine receptor modulators}}

{{Xenobiotic-sensing receptor modulators}}

[[Category:1-Phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines]]

[[Category:Chloroarenes]]

[[Category:Dopamine antagonists]]

[[Category:Experimental drugs]]