Identification

Name
Lorpiprazole
Accession Number
DB09195
Type
Small Molecule
Groups
Approved
Description

Lorpiprazole is a serotonin antagonist and reuptake inhibitor used for the treatment of major depressive disorder.[1] It is a piperazinyl-triazole derivative.[3]

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Normarex
Categories
UNII
0M14O7T47Q
CAS number
108785-69-9
Weight
Average: 405.469
Monoisotopic: 405.214030346
Chemical Formula
C21H26F3N5
InChI Key
BNRMWKUVWLKDQJ-YJBOKZPZSA-N
InChI
InChI=1S/C21H26F3N5/c22-21(23,24)16-4-2-5-17(13-16)28-11-9-27(10-12-28)8-7-19-25-26-20-18-6-1-3-15(18)14-29(19)20/h2,4-5,13,15,18H,1,3,6-12,14H2/t15-,18-/m0/s1
IUPAC Name
(1S,8R)-5-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-3,4,6-triazatricyclo[6.3.0.0²,⁶]undeca-2,4-diene
SMILES
[H][C@@]12CCC[C@]1([H])C1=NN=C(CCN3CCN(CC3)C3=CC=CC(=C3)C(F)(F)F)N1C2

Pharmacology

Indication

In 2016, lorpiprazole was classified in the "Chemical structure-related drug-like criteria of global approved drugs" as an antipsychotic and anxiolytic.[6] An antipsychotic is a medication used to treat a state of delusion, hallucination, paranoia or disordered thought. On the other hand, an anxiolytic is a medication used for the treatment of severe, chronic or debilitating anxiety. The anxiety state can be defined as an unpleasant state of tension, apprehension or uneasiness.[4]

Pharmacodynamics

Drugs like lorpiprazole that fit in the category of serotonin antagonists and reuptake inhibitors present a wide variety of effects when administered. They inhibit serotonin receptors like 5-HT2A as well as prevent the reuptake of serotonin, norepinephrine and dopamine. Additionally, they antagonize some adrenergic receptors. This diverse functional profile allows lorpiprazole to have a large therapeutic spectrum from symptom control as an adjuvant of other drugs to control of depressive syndromes as a monotherapy.[2]

Mechanism of action

Lorpiprazole is a serotonin antagonist and reuptake inhibitor thus, its activity is performed by antagonizing the 5-HT2A and the 5-HT2C serotoninergic receptors as well as the alpha1 and alpha2 adrenergic receptors, H1 histaminergic receptors and at high doses, inhibiting the SERT serotonin transporter.[2]

TargetActionsOrganism
A5-hydroxytryptamine receptor 2A
antagonist
Human
A5-hydroxytryptamine receptor 2C
antagonist
Human
AAlpha-1 adrenergic receptors
antagonist
Human
AAlpha-2 adrenergic receptors
antagonist
Human
AHistamine H1 receptor
antagonist
Human
ASodium-dependent serotonin transporter
antagonist
Human
Absorption

After oral administration, the serotonin antagonist and reuptake inhibitors are rapidly absorbed in the gastrointestinal tract. This absorption can be slow down depending on the type of diet. The maximum plasma concentration of this kind of drugs occurs approximately 1 hour after administration.[5]

Volume of distribution

The serotonin antagonists and reuptake inhibitors as lorpiprazole are quickly distributed through the blood-brain-barrier getting concentrated in the brain to even higher levels than the ones found in plasma.[5]

Protein binding

The plasma protein binding of serotonin antagonists and reuptake inhibitors like lorpiprazole is expected to be very high and correspond to even 89-99% of the administered dose.[5]

Metabolism

Serotonin antagonists and reuptake inhibitors like lorpiprazole are metabolized in the liver by the CYP450 isoenzymes, mainly CYP2D6 and CYP3A4.[2]

Route of elimination

The elimination of drugs that fit in the category of serotonin antagonists and reuptake inhibitors like lorpiprazole is expected to have a biphasic profile in which most of the metabolized drug should be disposed of by the urine.[5]

Half life

The estimated half-life for drugs like lorpiprazole, a serotonin antagonist and reuptake inhibitor, is in the range of 11-23 hours.[5]

Clearance
Not Available
Toxicity

The serotonin antagonists and reuptake inhibitors' side effects are minor with rare reports of cardiotoxicity. They have been reported to cause an unbalance between the sympathetic and parasympathetic system. There are also reports regarding a potential hepatotoxic effect of this drugs.[5]

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

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may decrease the sedative activities of Lorpiprazole.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may decrease the sedative activities of Lorpiprazole.
3,4-Methylenedioxyamphetamine3,4-Methylenedioxyamphetamine may decrease the sedative activities of Lorpiprazole.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may decrease the sedative activities of Lorpiprazole.
7-NitroindazoleThe serum concentration of 7-Nitroindazole can be increased when it is combined with Lorpiprazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of serotonin syndrome can be increased when Lorpiprazole is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Lorpiprazole.
AbirateroneThe serum concentration of Abiraterone can be increased when it is combined with Lorpiprazole.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Lorpiprazole.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Lorpiprazole.
Food Interactions
Not Available

References

General References
  1. Fagiolini A, Comandini A, Catena Dell'Osso M, Kasper S: Rediscovering trazodone for the treatment of major depressive disorder. CNS Drugs. 2012 Dec;26(12):1033-49. doi: 10.1007/s40263-012-0010-5. [PubMed:23192413]
  2. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]
  3. Elks J. and Ganellin C.R. (1990). The dictionary of drugs. Springer Science.
  4. Clark M., Harvey R., Finkel R., Rey J. and Whalen K. (2011). Pharmacology (5th ed.). Lippincott Williams & Wilkins.
  5. Szyndler J., Skorzewska A. and Plaznik A. (2003). Pharmacotherapy in psychiatry and neurology (3rd ed.). Institute of psychiatry and neurology.
  6. Molecules 2016 [Link]
External Links
PubChem Compound
20055414
PubChem Substance
310265103
ChemSpider
16736802
Wikipedia
Lorpiprazole

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)138 ºCElks J. The Dictionary of Drugs. (1990)
logP3.02DrugCentral
logS-3.63DrugCentral
Predicted Properties
PropertyValueSource
Water Solubility0.095 mg/mLALOGPS
logP3.64ALOGPS
logP3.22ChemAxon
logS-3.6ALOGPS
pKa (Strongest Basic)7.57ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area37.19 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity108.4 m3·mol-1ChemAxon
Polarizability42.08 Å3ChemAxon
Number of Rings5ChemAxon
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 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 / Trifluoromethylbenzenes / Dialkylarylamines / Aniline and substituted anilines / N-alkylpiperazines / Aralkylamines / Triazoles / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds
show 4 more
Substituents
Phenylpiperazine / N-arylpiperazine / Trifluoromethylbenzene / Tertiary aliphatic/aromatic amine / Aniline or substituted anilines / Dialkylarylamine / N-alkylpiperazine / Aralkylamine / Monocyclic benzene moiety / Benzenoid
show 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

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. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]
Kind
Protein
Organism
Human
Pharmacological action
Yes
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, 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. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]
Kind
Protein group
Organism
Human
Pharmacological action
Yes
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. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]
Kind
Protein group
Organism
Human
Pharmacological action
Yes
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. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
References
  1. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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. Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jablonska J, Rybakowski J: [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed:22232986]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Drug created on October 16, 2015 15:28 / Updated on August 02, 2018 06:15