Identification

Name
Pirlindole
Accession Number
DB09244
Type
Small Molecule
Groups
Approved
Description

Pirlindole is a reversible inhibitor of monoamine oxidase A (RIMA) which was developed and is currently used in Russia as an antidepressant. It is structurally and pharmacologically related to metralindole.

Pirlindole is a selective, reversible inhibitor of monoamine oxidase (MAO) subtype A (MAO-A) that is approved in several European and non-European countries for the treatment of major depression. The antidepressant efficacy and safety of pirlindole have been demonstrated in numerous studies and, supported by many years of clinical experience in the treatment of depression. Pirlindole's efficacy and safety have also been shown in the treatment of fibromyalgia.

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Lifril / Pyrazidol
Categories
UNII
V39YPH45FZ
CAS number
60762-57-4
Weight
Average: 226.323
Monoisotopic: 226.146998588
Chemical Formula
C15H18N2
InChI Key
IWVRVEIKCBFZNF-UHFFFAOYSA-N
InChI
InChI=1S/C15H18N2/c1-10-5-6-14-12(9-10)11-3-2-4-13-15(11)17(14)8-7-16-13/h5-6,9,13,16H,2-4,7-8H2,1H3
IUPAC Name
12-methyl-1,4-diazatetracyclo[7.6.1.0⁵,¹⁶.0¹⁰,¹⁵]hexadeca-9(16),10,12,14-tetraene
SMILES
CC1=CC=C2N3CCNC4CCCC(=C34)C2=C1

Pharmacology

Indication

For the treatment of major depression.

It is being studied in the treatment of fibromyalgia pain syndrome. One study determined that the effect of pirlindole on sensorimotor performance while driving a motor vehicle shows many similarities to that of placebo. The drug appears to stimulate the central nervous system, rather than exhibit a sedative effect, like many antidepressants. Because of its selective, reversible inhibition of monoamine oxidase (MAO-A) and short half-life, unpleasant "cheese effects" are avoided. This refers to the effects of consuming tyramine-rich foods, such as cheese while medicated with monoamine oxidase inhibitors, leading to severe headaches and hypertension [6]. of The available evidence supports pirlindole as a safe and effective treatment option for the management of depression and fibromyalgia syndrome [5].

Pharmacodynamics

Pirlindole regulates that metabolism of norepinephrine and catecholamines, leading to relief of depressive symptoms. The prevention of breakdown of these neuromodulators is thought to elevate mood.

Mechanism of action

This drug is a selective and reversible inhibitor of monoamine oxidase A (also known as MAO-A). Its main mechanism of action is selective and reversible inhibition of monoamine oxidase A. Its secondary mechanism of action is the inhibition effect of noradrenaline and 5-hydroxytryptamine reuptake [2].

TargetActionsOrganism
UAmine oxidase [flavin-containing] A
antagonist
Human
U5-hydroxytryptamine receptor 1A
antagonist
Human
UAlpha-2A adrenergic receptor
antagonist
Human
Absorption

Well absorbed with a bioavailability of 90% [3].

Volume of distribution
Not Available
Protein binding

97% binding to plasma proteins

Metabolism

The drug is metabolized significantly through the hepatic system. From studies in dogs and rats, pirlindole has a bioavailability of between 20 and 30% due to the hepatic first-pass effect on this medication [2]. The rat eliminates mainly unconjugated drug while the dog eliminates mostly conjugated drug [2].

Route of elimination

Mainly renal, with 0.4-0.5% being excreted in the urine as unchanged drug in healthy males [3]. Renal excretion was the main route of elimination of the metabolites in man [3].

Half life

0.7±0.3 in one study of healthy volunteers [3]

Clearance

High plasma clearance (450–1000 1/h) [3] in one study.

Toxicity

Short-acting selective and reversible monoamine oxidase A inhibitors, such as pirlindole, are commonly well-tolerated during an overdose. When taken alone, the clinical course is usually well-tolerated and benign.

Deaths from an overdose of this medication have more commonly observed during interactions with tyramine-rich foods tricyclic antidepressants (TCAs), or sympathomimetic drugs, and selective serotonin reuptake inhibitors (SSRIs). The clinical course of adverse effects from these conditions includes agitation, extreme tremor, followed by seizures and hyperthermia. Deaths occurred 3-16 hours after ingestion, after intractable seizure and/or hyperthermia and its sequelae, such as disseminated intravascular coagulation (DIC) and multi-organ failure [7].

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

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetaminePirlindole may increase the hypertensive activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Pirlindole.
3,4-MethylenedioxyamphetaminePirlindole may increase the hypertensive activities of 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetaminePirlindole may increase the hypertensive activities of 4-Bromo-2,5-dimethoxyamphetamine.
4-MethoxyamphetaminePirlindole may increase the hypertensive activities of 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe metabolism of 5-methoxy-N,N-dimethyltryptamine can be decreased when combined with Pirlindole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolinePirlindole may increase the hypertensive activities of 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbediterolThe risk or severity of adverse effects can be increased when Pirlindole is combined with Abediterol.
AcarbosePirlindole may increase the hypoglycemic activities of Acarbose.
AcebutololPirlindole may increase the hypotensive activities of Acebutolol.
Food Interactions
Not Available

References

Synthesis Reference

http://www.biomedsearch.com/nih/Pirlindole-in-treatment-depression-meta/21053988.html

General References
  1. Branco JC, Tome AM, Cruz MR, Filipe A: Pirlindole in the treatment of depression and fibromyalgia syndrome. Clin Drug Investig. 2011 Oct 1;31(10):675-89. doi: 10.2165/11595410-000000000-00000. [PubMed:21877764]
  2. Bruhwyler J, Liegeois JF, Geczy J: Pirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties. Pharmacol Res. 1997 Jul;36(1):23-33. doi: 10.1006/phrs.1997.0196. [PubMed:9368911]
  3. Psychiatry: The State of the Art Volume 3 Pharmacopsychiatry [Link]
  4. Chemistry Dashboard- Pirlindole [Link]
  5. Pirlindole in the Treatment of Depression and Fibromyalgia Syndrome [Link]
  6. Hypertensive effect and cheese [Link]
  7. Monamine oxide inhibitors [Link]
External Links
KEGG Drug
D08392
PubChem Compound
68802
PubChem Substance
310265147
ChemSpider
62039
ChEBI
91755
ChEMBL
CHEMBL32350
Wikipedia
Pirlindole

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)145 [L1393]
boiling point (°C)369 [L1393]
water solubility1.68e-02[L1393]
logP2.80[L1393]
Predicted Properties
PropertyValueSource
Water Solubility0.107 mg/mLALOGPS
logP2.1ALOGPS
logP3.1ChemAxon
logS-3.3ALOGPS
pKa (Strongest Basic)8.38ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area16.96 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity70.42 m3·mol-1ChemAxon
Polarizability27.27 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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 carbazoles. These are compounds containing a three ring system containing a pyrrole ring fused on either side to a benzene ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Carbazoles
Direct Parent
Carbazoles
Alternative Parents
3-alkylindoles / Aralkylamines / Benzenoids / Pyrroles / Heteroaromatic compounds / Dialkylamines / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Carbazole / 3-alkylindole / Indole / Aralkylamine / Benzenoid / Heteroaromatic compound / Pyrrole / Azacycle / Secondary amine / Secondary aliphatic amine
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
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. Bruhwyler J, Liegeois JF, Geczy J: Pirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties. Pharmacol Res. 1997 Jul;36(1):23-33. doi: 10.1006/phrs.1997.0196. [PubMed:9368911]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
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. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
References
  1. Bruhwyler J, Liegeois JF, Geczy J: Pirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties. Pharmacol Res. 1997 Jul;36(1):23-33. doi: 10.1006/phrs.1997.0196. [PubMed:9368911]
Kind
Protein
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...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. (r)-pirlindole and its pharmaceutically acceptable salts for use in medicine [Link]

Enzymes

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. Branco JC, Tome AM, Cruz MR, Filipe A: Pirlindole in the treatment of depression and fibromyalgia syndrome. Clin Drug Investig. 2011 Oct 1;31(10):675-89. doi: 10.2165/11595410-000000000-00000. [PubMed:21877764]

Drug created on October 23, 2015 16:13 / Updated on August 02, 2018 06:16