Perospirone targets multiple neurotransmitter receptors in the central nervous system. It acts as a potent antagonist at dopamine D₂ receptors (Ki = 0.6 nM) and serotonin 5-HT₂A receptors (Ki = 0.6 nM), which are believed to underlie its antipsychotic efficacy. The compound also exhibits high affinity for 5-HT₁A receptors (Ki = 2.5 nM), where it acts as a partial agonist, contributing to its anxiolytic and antidepressant effects. Additionally, Perospirone shows moderate affinity for α₁-adrenergic and histamine H₁ receptors, which may contribute to its side effect profile.

Significant affinity is exhibited by piperospirone (SM-9018 free base) for α1, 5-HT1, and D1 (Ki=17, 18, and 41 nM) [1].
In vitro, Perospirone has been characterized for its binding affinity and functional activity at various neurotransmitter receptors. The compound demonstrates high affinity for D₂, 5-HT₂A, and 5-HT₁A receptors, with Ki values in the low nanomolar range. In functional assays, Perospirone acts as a potent antagonist at D₂ and 5-HT₂A receptors and as a partial agonist at 5-HT₁A receptors. The compound's unique receptor profile, particularly its combined D₂/5-HT₂A antagonism and 5-HT₁A partial agonism, distinguishes it from other atypical antipsychotics.

Perospirone (SM-9018 free base; 1.0-10.0 mg/kg/day; disorder; for 14 days) significantly and dose-dependently reduced the cognitive abnormalities caused by PCP [2].
In vivo, Perospirone has demonstrated antipsychotic efficacy in various animal models. The compound inhibits apomorphine-induced stereotypy and climbing behavior in rodents, indicating D₂ receptor antagonism. It also reverses phencyclidine-induced hyperlocomotion and social interaction deficits, suggesting efficacy against negative and cognitive symptoms of schizophrenia. Perospirone has a lower propensity to induce catalepsy compared to typical antipsychotics, consistent with its lower risk of extrapyramidal side effects. These preclinical findings support its clinical use in schizophrenia.

In vitro receptor binding assays for Perospirone are performed using membrane preparations from cells expressing human recombinant receptors. Radiolabeled ligands, such as [³H]-spiperone for D₂ receptors and [³H]-ketanserin for 5-HT₂A receptors, are used in competition binding assays. The compound is incubated with the receptor membranes and the radioligand, and the bound radioactivity is measured using a scintillation counter. The Ki values are calculated from the displacement curves. Functional activity is assessed using second messenger assays, such as cAMP accumulation or calcium flux.

In vitro cellular experiments for Perospirone are performed using cell lines expressing human recombinant receptors. The compound's effects on receptor-mediated signaling pathways are assessed by measuring changes in intracellular cAMP levels (for D₂ and 5-HT₁A receptors) or calcium mobilization (for 5-HT₂A receptors). The potency and efficacy of Perospirone as an antagonist or agonist are determined from concentration-response curves. These experiments are essential for characterizing the compound's functional activity and selectivity.

Animal/Disease Models: Male ICR mice (6 weeks old) weighing 25-30 g[2]
Doses: 1.0, 3.0 or 10.0 mg/kg
Route of Administration: Oral; daily; 14 days
Experimental Results: In a dose-dependent manner Dramatically attenuated PCP-induced cognitive deficits in mice.
In vivo animal studies for Perospirone are conducted using rodent models. The compound is administered via intraperitoneal or oral routes. Antipsychotic efficacy is assessed using behavioral tests, including the apomorphine-induced climbing test, the conditioned avoidance response test, and the phencyclidine-induced hyperlocomotion test. The propensity for extrapyramidal side effects is assessed using the catalepsy test. The compound's effects on cognitive function and social interaction are evaluated using the novel object recognition test and the social interaction test.

Absorption, Distribution and Excretion
Following oral administration, peropyron is rapidly absorbed, reaching peak plasma concentrations in 0.8 to 1.5 hours. A single oral dose of 8 mg peropyron results in a peak plasma concentration of 5.7 μg/L. Repeated administration of peropyron has not been reported to result in accumulation. Peropyron is primarily excreted via the kidneys. After an oral dose of 8 mg peropyron, 0.4% of the total dose is excreted unchanged. Following a daily oral dose of 32 mg peropyron, the mean volume of distribution is 1733 L, ranging from 356 to 5246 L. Studies have shown that peropyron can cross the placenta and be secreted into the milk of pregnant rats. In patients who received a single oral dose of 8 mg peropyron, the apparent clearance was approximately 425.5 ± 150.3 L/h.

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Metabolism/Metabolites
Piropilone undergoes rapid and extensive first-pass metabolism in the liver; its metabolic pathways include hydroxylation, N-dealkylation, and S-oxidation, catalyzed by CYP1A1, 2C8, 2D6, and 3A4. CYP3A4 has been reported to contribute the most to pipelopone metabolism. Hydroxypilopone is formed by the partial hydroxylation of cyclohexane-1,2-dicarboximide, retaining its antiserotonergic pharmacological activity but with lower affinity.

Known metabolites of piperobelone include: 4,5,6,7-tetrahydro-2-[4-[4-(1,2-benzisothiazol-3-yl)piperazinyl]butyl]-2H-isoindol-1,3-dione, (3As,7aS)-2-[4-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]butyl]-7a-hydroxy-4,5,6,7-tetrahydro-3aH-isoindol-1,3-dione, 3-(1-piperazinyl)-1,2-benzisothiazol, (3aS,7aR)-2-[4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl]-5-hydroxy-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione and (3aS,7aR)-2-(4-hydroxybutyl)-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione.

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Biological half-life
After oral administration of 8 mg of piperoprinone, the elimination half-life is approximately 1.9 hours.

Perospirone exhibits favorable pharmacokinetic properties following oral administration. The compound is rapidly absorbed, with peak plasma concentrations achieved within 1-2 hours. It has a half-life of approximately 6-8 hours, allowing for twice-daily dosing. Perospirone is extensively metabolized in the liver, primarily by cytochrome P450 enzymes, and its metabolites are excreted via the biliary and renal routes. The compound's pharmacokinetic profile supports its clinical use in the treatment of schizophrenia.

Protein Binding
The plasma protein binding rate is 92%, with extensive binding to serum albumin and α1-acid glycoprotein.
The toxicity profile of Perospirone has been characterized in preclinical and clinical studies. Common adverse effects include insomnia, somnolence, and akathisia, which are consistent with its receptor profile. Perospirone has a lower propensity for extrapyramidal side effects and hyperprolactinemia compared to typical antipsychotics, which is attributed to its 5-HT₂A antagonism and 5-HT₁A partial agonism. The compound's safety in humans has been established through its clinical use in Japan, where it is approved for the treatment of schizophrenia.

[1]. Binding profile of SM-9018, a novel antipsychotic candidate. pn J Pharmacol. 1990 Dec;54(4):478-81.

[2]. Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone: role of serotonin 5-HT1A receptors. Eur Neuropsychopharmacol. 2008 Jun;18(6):448-54.

(3aR,7aS)-2-[4-[4-(1,2-benzothiazol-3-yl)-1-piperazinyl]butyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione is an N-arylpiperazine compound. Piperipelone is an atypical or second-generation antipsychotic drug belonging to the azaspirone class. It antagonizes serotonin 5-HT2A receptors and dopamine D2 receptors. It also has an affinity for 5-HT1A receptors and is a partial agonist. Piperipelone was developed in Japan in 2001 by Sumitomo Pharmaceuticals of Dai Nippon for the treatment of acute schizophrenia, bipolar disorder with mania, and chronic schizophrenia. It is usually available in hydrated hydrochloride form. Piperipelone is classified as an antipsychotic and has been shown to be effective for positive, negative, and general symptoms in patients with schizophrenia. Compared to [DB00502], perropirone also has fewer extrapyramidal side effects. Drug Indications For the treatment of schizophrenia and acute manic episodes of bipolar disorder. Mechanism of Action Perropirone alleviates positive symptoms of schizophrenia, such as delusions, hallucinations, and thought disorders, by antagonizing D2 receptors. Perropirone targets the mesolimbic pathway, reversing excessive dopaminergic signaling through D2 receptors. 5-HT2A receptor antagonism is thought to alleviate negative symptoms and cognitive impairment in schizophrenia. These receptors are Gi/Go-coupled receptors, and their activation leads to reduced neurotransmitter release and neuronal inhibition, thus playing a role in the regulation of dopamine release. Perropirone targets these receptors in the nigrostriatal pathway to reduce dopamine release and function. Conversely, 5-HT2A receptor antagonists may improve negative symptoms by enhancing dopamine and glutamate release in the mesocortical pathway. Activation of the 5-HT1A receptor further inhibits the release of 5-HT into the synaptic cleft.

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Pharmacodynamics
According to receptor binding assays, perropillone is a 5-HT2 receptor inverse agonist and a dopamine D2 receptor antagonist, binding with both receptors with high affinity. Perropillone is also a partial agonist of the 5-HT1A receptor, an autoreceptor that stimulates 5-HT uptake and inhibits 5-HT release. It also interacts as an antagonist with D4 and α₁-adrenergic receptors and as an inverse agonist with histamine H1 receptors. Binding to these receptors may explain its sedative and hypotensive effects. Perropillone has a low affinity for the D1 receptor, which is of little clinical significance.
Perospirone is an atypical antipsychotic agent approved for the treatment of schizophrenia in Japan. Its unique pharmacological profile, characterized by potent D₂ and 5-HT₂A antagonism and 5-HT₁A partial agonism, contributes to its efficacy against both positive and negative symptoms of schizophrenia, with a favorable side effect profile. Perospirone represents an important therapeutic option for patients with schizophrenia, particularly those who are intolerant to other antipsychotics. Its clinical use is supported by extensive preclinical and clinical data demonstrating its efficacy and safety.

C23H30N4O2S

426.5749

440.224

150915-41-6

Perospirone hydrochloride;129273-38-7

115368

Light yellow to yellow solid powder

1.4±0.1 g/cm3

648.8±65.0 °C at 760 mmHg

95-97 as hydrochloride form

346.2±34.3 °C

0.0±1.9 mmHg at 25°C

1.702

1.85

0

6

6

30

615

2

C1CC[C@H]2[C@@H](C1)C(=O)N(C2=O)CCCCN3CCN(CC3)C4=NSC5=CC=CC=C54

FBVFZWUMDDXLLG-HDICACEKSA-N

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+

(3aS,7aR)-2-[4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl]-3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~5 mg/mL (~11.72 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)