Identification

Name
Zimelidine
Accession Number
DB04832
Type
Small Molecule
Groups
Withdrawn
Description

Zimelidine has been banned worldwide due to serious, sometimes fatal, cases of central and/or peripheral neuropathy known as Guillain-Barré syndrome and due to a peculiar hypersensitivity reaction involving many organs including skin exanthema, flu-like symptoms, arthralgias, and sometimes eosinophilia. Additionally, zimelidine was charged to cause an increase in suicidal ideation and/or attempts among depressive patients. After its ban, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs.

Structure
Thumb
Synonyms
  • (Z)-3-(4'-Bromophenyl)-3-(3''-pyridyl)dimethylallylamine
  • (Z)-3-[1-(p-Bromophenyl)-3-(dimethylamino)propenyl]pyridine
  • (z)-zimelidine
  • Cis-zimelidine
  • Zimeldine
Categories
UNII
3J928617DW
CAS number
56775-88-3
Weight
Average: 317.224
Monoisotopic: 316.057511201
Chemical Formula
C16H17BrN2
InChI Key
OYPPVKRFBIWMSX-SXGWCWSVSA-N
InChI
InChI=1S/C16H17BrN2/c1-19(2)11-9-16(14-4-3-10-18-12-14)13-5-7-15(17)8-6-13/h3-10,12H,11H2,1-2H3/b16-9-
IUPAC Name
[3-(4-bromophenyl)-3-(pyridin-3-yl)prop-2-en-1-yl]dimethylamine
SMILES
CN(C)CC=C(C1=CC=C(Br)C=C1)C1=CN=CC=C1

Pharmacology

Indication

For the treatment of depression.

Pharmacodynamics

Zimelidine was the first marketed selective serotonin reuptake inhibitor (SSRI) antidepressant. It is a pyridylallylamine, structurally different from other antidepressants.

Mechanism of action

The antidepressant actions of zimelidine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Zimelidine blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT1A autoreceptors. SSRIs bind with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs.

TargetActionsOrganism
USodium-dependent serotonin transporterNot AvailableHuman
UAmine oxidase [flavin-containing] B
inhibitor
Human
UAmine oxidase [flavin-containing] A
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

8.4 +/- 2.0 hours for the parent compound and 19.4 +/- 3.6 hours for norzimelidine.

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

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Zimelidine.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the serotonergic activities of Zimelidine.
AbciximabZimelidine may increase the antiplatelet activities of Abciximab.
AcarboseZimelidine may increase the hypoglycemic activities of Acarbose.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Zimelidine.
AceclofenacZimelidine may increase the antiplatelet activities of Aceclofenac.
AcenocoumarolZimelidine may increase the antiplatelet activities of Acenocoumarol.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Zimelidine.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Zimelidine.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Zimelidine.
Food Interactions
Not Available

References

General References
  1. Caille G, Kouassi E, de Montigny C: Pharmacokinetic study of zimelidine using a new GLC method. Clin Pharmacokinet. 1983 Nov-Dec;8(6):530-40. [PubMed:6228368]
  2. Godbout R, Montplaisir J: The effect of zimelidine, a serotonin-reuptake blocker, on cataplexy and daytime sleepiness of narcoleptic patients. Clin Neuropharmacol. 1986;9(1):46-51. [PubMed:2950994]
External Links
PubChem Compound
41987
PubChem Substance
46504589
ChemSpider
4517305
BindingDB
50020706
ChEBI
135357
ChEMBL
CHEMBL37744
Wikipedia
Zimelidine
ATC Codes
N06AB02 — Zimeldine

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
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0239 mg/mLALOGPS
logP3.39ALOGPS
logP3.51ChemAxon
logS-4.1ALOGPS
pKa (Strongest Basic)8.62ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area16.13 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity93.94 m3·mol-1ChemAxon
Polarizability30.96 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.972
Blood Brain Barrier+0.9382
Caco-2 permeable+0.7284
P-glycoprotein substrateSubstrate0.6049
P-glycoprotein inhibitor INon-inhibitor0.8435
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterInhibitor0.5919
CYP450 2C9 substrateNon-substrate0.8893
CYP450 2D6 substrateNon-substrate0.6656
CYP450 3A4 substrateSubstrate0.5541
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorInhibitor0.8949
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorInhibitor0.796
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8185
Ames testNon AMES toxic0.8077
CarcinogenicityNon-carcinogens0.807
BiodegradationNot ready biodegradable0.9964
Rat acute toxicity2.5787 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8348
hERG inhibition (predictor II)Inhibitor0.6614
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 styrenes. These are organic compounds containing an ethenylbenzene moiety.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Styrenes
Direct Parent
Styrenes
Alternative Parents
Bromobenzenes / Pyridines and derivatives / Aryl bromides / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Organobromides / Hydrocarbon derivatives
Substituents
Styrene / Bromobenzene / Halobenzene / Aryl bromide / Aryl halide / Pyridine / Heteroaromatic compound / Tertiary aliphatic amine / Tertiary amine / Organoheterocyclic compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. 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]
  4. Sugimoto Y, Inoue K, Yamada J: Involvement of serotonin in zimelidine-induced hyperglycemia in mice. Biol Pharm Bull. 1999 Nov;22(11):1240-1. [PubMed:10598036]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Primary amine oxidase activity
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOB
Uniprot ID
P27338
Uniprot Name
Amine oxidase [flavin-containing] B
Molecular Weight
58762.475 Da
References
  1. Egashira T, Takayama F, Yamanaka Y: The inhibition of monoamine oxidase activity by various antidepressants: differences found in various mammalian species. Jpn J Pharmacol. 1999 Sep;81(1):115-21. [PubMed:10580379]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOA
Uniprot ID
P21397
Uniprot Name
Amine oxidase [flavin-containing] A
Molecular Weight
59681.27 Da
References
  1. Egashira T, Takayama F, Yamanaka Y: Effects of long-term treatment with dicyclic, tricyclic, tetracyclic, and noncyclic antidepressant drugs on monoamine oxidase activity in mouse brain. Gen Pharmacol. 1996 Jul;27(5):773-8. [PubMed:8842678]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Gerotziafas GT, Mahe I, Elalamy I: New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients. Ther Clin Risk Manag. 2014 Jun 13;10:423-36. doi: 10.2147/TCRM.S49063. eCollection 2014. [PubMed:24966680]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW: Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37. [PubMed:12438524]

Drug created on September 11, 2007 15:01 / Updated on October 01, 2018 13:56