Identification

Name
Etoperidone
Accession Number
DB09194
Type
Small Molecule
Groups
Withdrawn
Description

Etoperidone is an atypical antidepressant introduced in Europe in 1977. It is a phenylpiperazine-substituted triazole derivative with a composition that classifies it as an analog of tradozone and presents a similar pharmacological profile.[6] Etoperidone was developed by Angelini Francesco ACRAF and even nowadays, there is uncertanty if this drug ever reached the market.[2]

Structure
Thumb
Synonyms
Not Available
External IDs
ST-1191
Product Ingredients
IngredientUNIICASInChI Key
Etoperidone hydrochloride2FSU2FR80J57775-22-1BHKPQZVLIZKSAG-UHFFFAOYSA-N
International/Other Brands
Axiomin (Promeco) / Depracer (L. Lepori, Lda.) / Etonin / Etoran (II Dong) / Staff (Sigma-Tau) / Tropene (Degussa)
Categories
UNII
KAI6MVO39Z
CAS number
52942-31-1
Weight
Average: 377.92
Monoisotopic: 377.1982382
Chemical Formula
C19H28ClN5O
InChI Key
IZBNNCFOBMGTQX-UHFFFAOYSA-N
InChI
InChI=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
IUPAC Name
1-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-3,4-diethyl-4,5-dihydro-1H-1,2,4-triazol-5-one
SMILES
CCN1C(=O)N(CCCN2CCN(CC2)C2=CC=CC(Cl)=C2)N=C1CC

Pharmacology

Indication

Etoperidone has been studied for the treatment of depression[8], tremors in Parkinson, extrapyramidal symptoms[11] and male impotence[12]. It is not certain if it was ever approved and marketed but its current status is withdrawn.

Pharmacodynamics

Etoperidone has a biphasic effect on the central transmission of serotonin.[6] It presents the capacity to inhibit serotonin receptor but also to inhibit the reuptake of serotonin, norepinephrine and dopamine.[7] As part of its actions, etoperidone also inhibits the α-adrenergic receptors which directly corresponds to the sedative and cardiovascular effects.[6, 9] The presence of both effects caused that the effective dose of etoperidone was poorly tolerated thus, efforts have been made to separate the serotonergic and adrenergic functions in order to generate etoperidone-derivatives like nefazodone.[9]

Mechanism of action

The activity of etoperidone is made mainly by its major metabolite 1-(3'-chlorophenyl)piperazine (mCPP). mCPP binds with different affinity to most of the serotonergic receptors and adrenergic receptors. This metabolite is an agonist of 5-HT2c and an antagonist of 5-HT2a. Part of etoperidone structure contibutes to the activity in the α-adrenergic receptors.[9]

TargetActionsOrganism
UAlpha-1 adrenergic receptors
antagonist
Human
UAlpha-2 adrenergic receptors
antagonist
Human
UD(2) dopamine receptor
antagonist
Human
UMuscarinic acetylcholine receptor
antagonist
Human
A5-hydroxytryptamine receptor 2A
antagonist
Human
A5-hydroxytryptamine receptor 2C
agonist
Human
Absorption

The absorption and bioavailability is highly variable between individuals and can be as low as 12%. The lower bioavailability is explained due to its high metabolism.[5] The mean time to peak plasma concentration is ranged from 1.4-4.8 hours.[10]

Volume of distribution

The high protein binding presented in etoperidone modulates its volume of distribution to a range of 0.23 to 0.69 L/kg.[13]

Protein binding

Etoperidone presents an extensive plasma protein binding.[13]

Metabolism

Etoperidone is highly metabolized and it forms 21 different metabolites that can be found in plasma, urine and faeces. The metabolism of etoperidone is thought to be related to 5 different reaction pathways that are alkyl oxidation, piperazinyl oxidation, N-dealkylation, phenyl hydroxylation and conjugation.[4]

Route of elimination

The elimination of an oral dose of etoperidone presents a division of 78.8% found in urine and 9.6% found in faeces. On the elimination route, less than 0.01% of the etoperidone dose is represented by the unchanged drug while the rest is formed by 21 different metabolites.[4]

Half life

After oral administration of etoperidone the terminal half-life was 21.7 hours.[4]

Clearance

The apparent clearance of etoperidone was 1.01 ml/min.[4]

Toxicity

Etoperidone presented major cardiovascular effects recorded as abnormal electrocardiogram, changes in blood pressure and even cardiac arrest. From the changes in blood pressure hypotension was the primary effect. These cardiovascular reactions are consistent with its effect to catecholamines.[5]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of adverse effects can be increased when Etoperidone is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Etoperidone is combined with (S)-Warfarin.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Etoperidone.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Etoperidone is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of serotonin syndrome can be increased when 3,4-Methylenedioxyamphetamine is combined with Etoperidone.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Etoperidone.
4-hydroxycoumarinThe risk or severity of adverse effects can be increased when Etoperidone is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Etoperidone.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Etoperidone is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Etoperidone.
Food Interactions
Not Available

References

General References
  1. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
  2. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  3. Costa A, Martignoni E, Blandini F, Petraglia F, Genazzani AR, Nappi G: Effects of etoperidone on sympathetic and pituitary-adrenal responses to diverse stressors in humans. Clin Neuropharmacol. 1993 Apr;16(2):127-38. [PubMed:8386590]
  4. Caldwell GW, Wu WN, Masucci JA: Evaluation of the absorption, excretion and metabolism of [14C] etoperidone in man. Xenobiotica. 2001 Nov;31(11):823-39. doi: 10.1080/00498250110091758 . [PubMed:11765144]
  5. Lisciani R, Baldini A, Benedetti D, Campana A, Barcellona PS: Acute cardiovascular toxicity of trazodone, etoperidone and imipramine in rats. Toxicology. 1978 Jun;10(2):151-8. [PubMed:684760]
  6. Ellis G.P. and West G.B. (1986). Progress in Medicinal Chemistry Volume 23 (pp. 159). Elsevier.
  7. Morrison-Valfre M. (2016). Foundations of Mental Health Care (pp. 245). Elsevier .
  8. Taylor and Francis (2000). Index Nominum 2000: International drug directory. Swiss Pharmaceutical Society.
  9. O'Brien R.A. (1986). Receptor Binding in drug research. Marcel Dekker Inc..
  10. Barceloux D.G. (2012). Medical toxicology of drug abuse: Synthesized chemicals and psychoactive plants.. Wiley.
  11. Patents [Link]
  12. Patents [Link]
  13. Not in Pubmed [Link]
External Links
PubChem Compound
40589
PubChem Substance
310265102
ChemSpider
37083
BindingDB
82438
ChEBI
135589
ChEMBL
CHEMBL1743259
Wikipedia
Etoperidone
ATC Codes
N06AB09 — Etoperidone
MSDS
Download (79 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)197-198 ºC"Drugs - Synonyms and Properties", Ashgate Publishing Co.
boiling point (°C)499ºC at 760mmHg"Drugs - Synonyms and Properties", Ashgate Publishing Co.
Predicted Properties
PropertyValueSource
Water Solubility0.425 mg/mLALOGPS
logP2.81ALOGPS
logP3.37ChemAxon
logS-3ALOGPS
pKa (Strongest Basic)7.09ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area42.39 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity106.57 m3·mol-1ChemAxon
Polarizability42.23 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
Phenylpiperazines
Alternative Parents
N-arylpiperazines / Dialkylarylamines / Aniline and substituted anilines / N-alkylpiperazines / Chlorobenzenes / Aryl chlorides / Triazoles / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds
show 5 more
Substituents
Phenylpiperazine / N-arylpiperazine / Tertiary aliphatic/aromatic amine / Dialkylarylamine / Aniline or substituted anilines / Chlorobenzene / Halobenzene / N-alkylpiperazine / Benzenoid / Aryl halide
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...

Components:
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
Kind
Protein group
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...

Components:
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Potassium channel regulator activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
Kind
Protein group
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...

Components:
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Virus receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
Gene Name
HTR2C
Uniprot ID
P28335
Uniprot Name
5-hydroxytryptamine receptor 2C
Molecular Weight
51820.705 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serotonin:sodium symporter activity
Specific Function
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
Gene Name
SLC6A4
Uniprot ID
P31645
Uniprot Name
Sodium-dependent serotonin transporter
Molecular Weight
70324.165 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Monoamine transmembrane transporter activity
Specific Function
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A3
Uniprot ID
Q01959
Uniprot Name
Sodium-dependent dopamine transporter
Molecular Weight
68494.255 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]

Drug created on October 16, 2015 15:21 / Updated on November 02, 2018 09:12