etoperidone

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 447570339

| IUPAC_name = 2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-4,5-diethyl-1,2,4-triazol-3-one

| image = Etoperidone structure.svg

| width = 250px

| tradename = Several

| synonyms = ST-1191; McN-A-2673-11

| pregnancy_category =

| legal_status =

| routes_of_administration = By mouth

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

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

| CAS_number = 52942-31-1

| ATC_prefix = N06

| ATC_suffix = AB09

| PubChem = 40589

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1743259

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank =

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 37083

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

| UNII = KAI6MVO39Z

| C=19 | H=28 | Cl=1 | N=5 | O=1

| SMILES = Clc3cccc(N2CCN(CCCN1/N=C(\N(C1=O)CC)CC)CC2)c3

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C19H28ClN5O/c1-3-18-21-25(19(26)24(18)4-2)10-6-9-22-11-13-23(14-12-22)17-8-5-7-16(20)15-17/h5,7-8,15H,3-4,6,9-14H2,1-2H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = IZBNNCFOBMGTQX-UHFFFAOYSA-N

}}

Etoperidone, associated with several brand names, is an atypical antidepressant which was developed in the 1970s and either is no longer marketed or was never marketed.{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA421|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|page=421}}{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1533|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1533–}}{{cite book| vauthors = Akritopoulou-Zanze I | chapter = Arylpiperazine-Based 5-HT1A Receptor Partial Agonists and 5-HT2A Antagonists for the Treatment of Autism, Depression, Anxiety, Psychosis, and Schizophrenia | veditors = Lamberth C, Dinges J |title=Bioactive Heterocyclic Compound Classes: Pharmaceuticals| chapter-url = https://books.google.com/books?id=35uKnWKD9V8C&pg=RA1-PA50|date=16 August 2012|publisher=John Wiley & Sons|isbn=978-3-527-66447-4|pages=81–97 | doi = 10.1002/9783527664450.ch6 }} It is a phenylpiperazine related to trazodone and nefazodone in chemical structure and is a serotonin antagonist and reuptake inhibitor (SARI) similarly to them.{{cite book| vauthors = Morrison-Valfre M |title=Foundations of Mental Health Care - E-Book|url=https://books.google.com/books?id=EFfoDAAAQBAJ&pg=PA245|date=23 August 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-37104-9|pages=245–}}

Medical uses

Etoperidone was used or was intended for use as an antidepressant in the treatment of depression.

Etoperidone might be useful as a hallucinogen antidote or "trip killer" in blocking the effects of serotonergic psychedelics like psilocybin and lysergic acid diethylamide (LSD).{{cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 | url = }}

Pharmacology

=Pharmacodynamics=

Site	K_i (nM)	Species	Ref
class="wikitable floatright" \|+ Etoperidone{{cite web \| title = PDSP K_i Database \| work = Psychoactive Drug Screening Program (PDSP)\|author1-link=Bryan Roth \| vauthors = Roth BL, Driscol J \| publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health \| access-date = 14 August 2017 \| url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=etoperidone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}
{{abbrlink\|SERT\|Serotonin transporter}}	890	Human	{{cite journal \| vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E \| title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters \| journal = Eur. J. Pharmacol. \| volume = 340 \| issue = 2–3 \| pages = 249–58 \| year = 1997 \| pmid = 9537821 \| doi = 10.1016/s0014-2999(97)01393-9}}
{{abbrlink\|NET\|Norepinephrine transporter}}	20,000	Human
{{abbrlink\|DAT\|Dopamine transporter}}	52,000	Human
5-HT_1A	85	Human	{{cite journal \| vauthors = Cusack B, Nelson A, Richelson E \| title = Binding of antidepressants to human brain receptors: focus on newer generation compounds \| journal = Psychopharmacology \| volume = 114 \| issue = 4 \| pages = 559–65 \| year = 1994 \| pmid = 7855217 \| doi = 10.1007/bf02244985\| s2cid = 21236268 }}
5-HT_2A	36	Human
5-HT_2C	?	?	?
α₁	38	Human
α₂	570	Human
D₂	2,300	Human
H₁	3,100	Human
{{abbrlink\|mACh\|Muscarinic acetylcholine receptor}}	>35,000	Human	{{cite journal \| vauthors = Stanton T, Bolden-Watson C, Cusack B, Richelson E \| title = Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics \| journal = Biochem. Pharmacol. \| volume = 45 \| issue = 11 \| pages = 2352–4 \| year = 1993 \| pmid = 8100134 \| doi = 10.1016/0006-2952(93)90211-e}}
class="sortbottom" \| colspan="4" style="width: 1px;" \| Values are K_i (nM). The smaller the value, the more strongly the drug binds to the site.

Etoperidone is as an antagonist of several receptors in the following order of potency: 5-HT_2A receptor (36 nM) > α₁-adrenergic receptor (38 nM) > 5-HT_1A receptor (85 nM) (may be a partial agonist) > α₂-adrenergic receptor (570 nM); it has only very weak or negligible affinity for blocking the following receptors: D₂ receptor (2,300 nM) > H₁ receptor (3,100 nM) > mACh receptors (>35,000 nM). In addition to its receptor blockade, etoperidone also has weak affinity for the monoamine transporters as well: serotonin transporter (890 nM) > norepinephrine transporter (20,000 nM) > dopamine transporter (52,000 nM).

=Pharmacokinetics=

Etoperidone is metabolized in part to meta-chlorophenylpiperazine (mCPP), which likely accounts for its serotonergic effects.{{cite journal | vauthors = Garattini S | title = Active drug metabolites. An overview of their relevance in clinical pharmacokinetics | journal = Clinical Pharmacokinetics | volume = 10 | issue = 3 | pages = 216–227 | date = 1985 | pmid = 2861928 | doi = 10.2165/00003088-198510030-00002 | s2cid = 21305772 }}{{cite journal | vauthors = Raffa RB, Shank RP, Vaught JL | title = Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity | journal = Psychopharmacology | volume = 108 | issue = 3 | pages = 320–326 | date = 1992 | pmid = 1387963 | doi = 10.1007/BF02245118 | s2cid = 24965789 }}

Chemistry

Etoperidone is a phenylpiperazine and is chemically related to nefazodone and trazodone.{{cite book| veditors = Dörwald FZ |title=Lead optimization for medicinal chemists : pharmacokinetic properties of functional groups and organic compounds|date=2012|publisher=Wiley-VCH|location=Weinheim|isbn=9783527645640|chapter=46. Arylalkylamines}}{{cite book| vauthors = Eison MS, Taylor DB, Riblet LA | veditors = Williams M, Malick JB |title=Drug Discovery and Development|date=1987|publisher=Springer Science & Business Media|isbn=9781461248286|page=390|chapter-url=https://books.google.com/books?id=O0LuBwAAQBAJ&pg=PA390|language=en|chapter=Atypical Psychotropic Agents}}

History

Etoperidone was discovered by scientists at Angelini, who also discovered trazodone.{{cite journal | vauthors = Silvestrini B | title = Trazodone and the mental pain hypothesis of depression | journal = Neuropsychobiology | volume = 15 | issue = Suppl 1 | pages = 2–9 | date = 1986 | pmid = 3014372 | doi = 10.1159/000118270 }} Its development names have included ST-1191 and McN-A-2673-11. The {{abbrlink|INN|International Nonproprietary Name}} etoperidone was proposed in 1976 and recommended in 1977.{{cite journal|title=Proposed INN List 36|journal=Supplement to the WHO Chronicle|date=1976|volume=30|issue=9|url=https://mednet-communities.net/inn/db/media/docs/p-innlist36.pdf}}{{cite journal|title=Recommended INN List 17|journal=Supplement to the WHO Chronicle|date=1977|volume=31|issue=10|url=https://mednet-communities.net/inn/db/media/docs/r-innlist17.pdf}} The drug was given brand names in Spain (Centren (Esteve) and Depraser (Lepori)) and Italy (Staff (Sigma Tau)) and was also given the brand names Axiomin and Etonin, but it is not entirely clear if it was actually marketed; the Pharmaceutical Manufacturing Encyclopedia provides no dates for commercial introduction.{{cite book| vauthors = McPherson EM |title=Pharmaceutical Manufacturing Encyclopedia.|date=2007|publisher=Elsevier|location=Burlington|isbn=978-0-8155-1856-3|page=1533|edition=3rd|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1533}} According to Micromedex's Index Nominum: International Drug Directory, etoperidone was indeed previously marketed in Spain and Italy.

Society and culture

=Generic names=

Etoperidone is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, while etoperidone hydrochloride is its {{abbrlink|USAN|United States Adopted Name}}.{{cite book| vauthors = Elks J |title = The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA527|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=527–}}{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA117|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=117–}}

=Brand names=

Etoperidone has been associated with the brand names Axiomin, Centren, Depraser, Etonin, and Staff.

Research

Etoperidone has been studied in dementia and found to be about as effective as thioridazine.{{cite journal | vauthors = Kirchner V, Kelly CA, Harvey RJ | title = Thioridazine for dementia | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD000464 | date = 2001 | pmid = 11686961 | pmc = 7034526 | doi = 10.1002/14651858.CD000464 }}