Identification

Name
Perospirone
Accession Number
DB08922
Type
Small Molecule
Groups
Approved
Description

Perospirone is an atypical or second-generation antipsychotic of the azapirone family that antagonizes serotonin 5HT2A receptors and dopamine D2 receptors. It also displays affinity towards 5HT1A receptors as a partial agonist. It was introduced in Japan by Dainippon Sumitomo Pharma in 2001 for the treatment of acute and chronic schizophrenia and acute cases of bipolar mania. It is commonly present as the hydrated hydrochloride salt form. Classified as a neuroleptic agent, perospirone is shown to be effective against positive, negative and general symptoms in patients with schizophrenia [1]. It is also shown to be less associated with extrapyramidal symptoms as a side effect compared to Haloperidol.

Structure
Thumb
Synonyms
  • cis-N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,2-cyclohexanedicarboximide
  • SM-9018
International/Other Brands
Lullan (Dainippon Sumitomo Pharma)
Categories
UNII
N303OK87DT
CAS number
150915-41-6
Weight
Average: 426.58
Monoisotopic: 426.208947396
Chemical Formula
C23H30N4O2S
InChI Key
FBVFZWUMDDXLLG-HDICACEKSA-N
InChI
InChI=1S/C23H30N4O2S/c28-22-17-7-1-2-8-18(17)23(29)27(22)12-6-5-11-25-13-15-26(16-14-25)21-19-9-3-4-10-20(19)30-24-21/h3-4,9-10,17-18H,1-2,5-8,11-16H2/t17-,18+
IUPAC Name
(3aR,7aS)-2-{4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl}-octahydro-1H-isoindole-1,3-dione
SMILES
[H][C@@]12CCCC[C@]1([H])C(=O)N(CCCCN1CCN(CC1)C1=NSC3=CC=CC=C13)C2=O

Pharmacology

Indication

For the treatment of schizophrenia and acute cases of bipolar mania.

Pharmacodynamics

Perospirone is a serotonin 5-HT2 receptor inverse agonist and dopamine D2 receptor antagonist based on receptor binding experiments [3, 4] that binds to both receptors with high affinity. Perospirone is also a partial agonist at 5-HT1A receptors which are autoreceptors that stimulate the uptake of 5-HT and inhibit 5-HT release [7]. It also interacts with D4 receptors and α₁-adrenergic receptors as an antagonist, as well as histamine H1 receptor an inverse agonist. Binding to these receptors may explain sedative and hypotensive actions. Perospirone binds to D1 receptors with low affinity and minimal clinical significance [4].

Mechanism of action

Antagonism at D2 receptors is believed to relieve the positive symptoms of schizophrenia such as delusions, hallucinations, and thought disorders. Perospirone targets the mesolimbic patway to reverse the overactivity of the dopaminergic signalling via D2 receptors [7]. 5-HT2A antagonism is thought to allevaite the negative symptoms and cognitive impairments of schizophrenia. These receptors are Gi/Go coupled receptors that lead to decreased neurotransmitter release and neuronal inhibition when activated, thus play a role in dopamine release regulation. Perospirone targets these receptors in the nigrostriatal pathway to reduce dopamine release and function. In contrast, 5-HT2A receptor antagonism may improve the negative symptoms by enhancing dopamine and glutamate release in the mesocortical pathway [7]. 5-HT1A receptor activation further inhibits the release of 5-HT into the synaptic cleft.

TargetActionsOrganism
A5-hydroxytryptamine receptor 2A
inverse agonist
Human
AD(2) dopamine receptor
antagonist
Human
A5-hydroxytryptamine receptor 1A
partial agonist
Human
UHistamine H1 receptor
inverse agonist
Human
UD(4) dopamine receptor
antagonist
Human
UAlpha-1 adrenergic receptors
antagonist
Human
Absorption

Perospirone is rapidly absorbed following oral administration with the time to reach peak plasma concentration of 0.8 to 1.5 hours. A single oral dose of 8mg perospirone results in peak plasma concentration of 5.7 ug/L [2]. Perospirone is not reported to be accumulated after repeated dosing.

Volume of distribution

The mean volume of distribution following oral administration of 32 mg/day of perospirone is 1733L, with values ranging from 356-5246 L. It is shown to cross the placenta and be secreted into milk in pregnant rats [1].

Protein binding

Plasma protein binding ratio is 92% with extensive binding to serum albumin and α1-acid glycoprotein [2].

Metabolism

Perospirone undergoes rapid and extensive first-pass metabolism in the liver; the metabolic pathways involve hydroxylation, N-dealkylation, and S-oxidation, which are catalyzed by CYP1A1, 2C8, 2D6, and 3A4. CYP3A4 is reported to have highest level of contribution in perospirone metabolism. Hydroxyperospirone is formed from hydroxylation of the the cyclohexane-1,2-dicarboximide moiety and retains pharmacological action by mediating antiserotonergic effects, although with lower affinity [1].

Route of elimination

Perospirone is mainly excreted via renal elimination. 0.4% of of total dose is excreted as unchanged drug following oral administration of 8mg perospirone [2].

Half life

The elimination half life is approximately 1.9 hours following oral ingestion of 8mg perospirone [2].

Clearance

Apparent clearance rate is approximately 425.5 ± 150.3 L/h in patients receiving a single oral dose of 8mg perospirone [6].

Toxicity

Frequently experienced adverse effects include extrapyramidal symptoms, insomnia, and drowsiness. More serious adverse effect include neuroleptic malignant syndrome [1]. Oral LD50 value in rats is 870 mg/kg [MSDS].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
5-hydroxytryptamine receptor 1A---(C;C)CC Allele (homozygous)Effect Directly StudiedThe presence of this polymorphism in HTR1A may indicate a higher level of efficacy in improving negative symptoms of schizophrenia when treated with perospirone.Details

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetaminePerospirone may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetaminePerospirone may decrease the stimulatory activities of 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetaminePerospirone may decrease the stimulatory activities of 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetaminePerospirone may decrease the stimulatory activities of 4-Bromo-2,5-dimethoxyamphetamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Perospirone.
AbirateroneThe serum concentration of Perospirone can be increased when it is combined with Abiraterone.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Perospirone.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Perospirone.
Acetyl sulfisoxazoleThe metabolism of Perospirone can be decreased when combined with Acetyl sulfisoxazole.
AdipiplonThe risk or severity of adverse effects can be increased when Adipiplon is combined with Perospirone.
Food Interactions
Not Available

References

General References
  1. Yasui-Furukori N, Furukori H, Nakagami T, Saito M, Inoue Y, Kaneko S, Tateishi T: Steady-state pharmacokinetics of a new antipsychotic agent perospirone and its active metabolite, and its relationship with prolactin response. Ther Drug Monit. 2004 Aug;26(4):361-5. [PubMed:15257064]
  2. Onrust SV, McClellan K: Perospirone. CNS Drugs. 2001;15(4):329-37; discussion 338. [PubMed:11463136]
  3. Hirose A, Kato T, Ohno Y, Shimizu H, Tanaka H, Nakamura M, Katsube J: Pharmacological actions of SM-9018, a new neuroleptic drug with both potent 5-hydroxytryptamine2 and dopamine2 antagonistic actions. Jpn J Pharmacol. 1990 Jul;53(3):321-9. [PubMed:1975278]
  4. Kishi T, Iwata N: Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2013 Sep;27(9):731-41. doi: 10.1007/s40263-013-0085-7. [PubMed:23812802]
  5. Takeuchi T, Furuta K, Hirasawa T, Masaki H, Yukizane T, Atsuta H, Nishikawa T: Perospirone in the treatment of patients with delirium. Psychiatry Clin Neurosci. 2007 Feb;61(1):67-70. [PubMed:17239041]
  6. Zou JJ, Liu L, Di B, Ding L, Zhu YB, Fan HW, Xiao DW, Wang GJ: Estimation of Perospirone in Human Plasma by LC–MS–MS and Its Application to Pharmacokinetics Study Chromatographia. 2008 August 1;68(3-4):239–243.
  7. 45. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 553-563). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
External Links
PubChem Compound
115368
PubChem Substance
310264903
ChemSpider
103202
ChEBI
94777
ChEMBL
CHEMBL1472975
Wikipedia
Perospirone
MSDS
Download (1.62 MB)

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)95-97 as hydrochloride formMSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0317 mg/mLALOGPS
logP3.94ALOGPS
logP3.74ChemAxon
logS-4.1ALOGPS
pKa (Strongest Basic)7.73ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area56.75 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity120.29 m3·mol-1ChemAxon
Polarizability48.39 Å3ChemAxon
Number of Rings5ChemAxon
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-0420900000-590f813b91a94ad578ab

Taxonomy

Description
This compound belongs to the class of organic compounds known as n-arylpiperazines. These are organic compounds containing a piperazine ring where the nitrogen ring atom carries an aryl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
N-arylpiperazines
Alternative Parents
Isoindolones / Benzothiazoles / Isoindoles / Dialkylarylamines / N-alkylpiperazines / Aminothiazoles / Benzenoids / Pyrrolidine-2-ones / Imidolactams / N-substituted carboxylic acid imides
show 11 more
Substituents
N-arylpiperazine / Isoindolone / 1,2-benzothiazole / Isoindoline / Isoindole / Isoindole or derivatives / Dialkylarylamine / N-alkylpiperazine / 1,2-thiazolamine / Carboxylic acid imide, n-substituted
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inverse agonist
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. Tanaka H, Ohno Y, Nakamura M: Localization and pharmacological characterization of [3H]perospirone-binding sites in rat brain. Gen Pharmacol. 1998 Jul;31(1):159-64. [PubMed:9595296]
  2. Kishi T, Iwata N: Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2013 Sep;27(9):731-41. doi: 10.1007/s40263-013-0085-7. [PubMed:23812802]
Kind
Protein
Organism
Human
Pharmacological action
Yes
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. Tanaka H, Ohno Y, Nakamura M: Localization and pharmacological characterization of [3H]perospirone-binding sites in rat brain. Gen Pharmacol. 1998 Jul;31(1):159-64. [PubMed:9595296]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Partial 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. 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. Shiwa T, Amano T, Matsubayashi H, Seki T, Sasa M, Sakai N: Perospirone, a novel antipsychotic agent, hyperpolarizes rat dorsal raphe neurons via 5-HT1A receptor. J Pharmacol Sci. 2003 Sep;93(1):114-7. [PubMed:14501160]
  2. Tanaka H, Ohno Y, Nakamura M: Localization and pharmacological characterization of [3H]perospirone-binding sites in rat brain. Gen Pharmacol. 1998 Jul;31(1):159-64. [PubMed:9595296]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inverse agonist
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. Kishi T, Iwata N: Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2013 Sep;27(9):731-41. doi: 10.1007/s40263-013-0085-7. [PubMed:23812802]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Sh3 domain binding
Specific Function
Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins ...
Gene Name
DRD4
Uniprot ID
P21917
Uniprot Name
D(4) dopamine receptor
Molecular Weight
48359.86 Da
References
  1. Kishi T, Iwata N: Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2013 Sep;27(9):731-41. doi: 10.1007/s40263-013-0085-7. [PubMed:23812802]
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. Kishi T, Iwata N: Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2013 Sep;27(9):731-41. doi: 10.1007/s40263-013-0085-7. [PubMed:23812802]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Yasui-Furukori N, Furukori H, Nakagami T, Saito M, Inoue Y, Kaneko S, Tateishi T: Steady-state pharmacokinetics of a new antipsychotic agent perospirone and its active metabolite, and its relationship with prolactin response. Ther Drug Monit. 2004 Aug;26(4):361-5. [PubMed:15257064]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Yasui-Furukori N, Furukori H, Nakagami T, Saito M, Inoue Y, Kaneko S, Tateishi T: Steady-state pharmacokinetics of a new antipsychotic agent perospirone and its active metabolite, and its relationship with prolactin response. Ther Drug Monit. 2004 Aug;26(4):361-5. [PubMed:15257064]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Yasui-Furukori N, Furukori H, Nakagami T, Saito M, Inoue Y, Kaneko S, Tateishi T: Steady-state pharmacokinetics of a new antipsychotic agent perospirone and its active metabolite, and its relationship with prolactin response. Ther Drug Monit. 2004 Aug;26(4):361-5. [PubMed:15257064]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d 24-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 oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Yasui-Furukori N, Furukori H, Nakagami T, Saito M, Inoue Y, Kaneko S, Tateishi T: Steady-state pharmacokinetics of a new antipsychotic agent perospirone and its active metabolite, and its relationship with prolactin response. Ther Drug Monit. 2004 Aug;26(4):361-5. [PubMed:15257064]

Drug created on September 21, 2013 15:35 / Updated on August 02, 2018 06:11