Significant affinity is exhibited by piperospirone (SM-9018 free base) for α1, 5-HT1, and D1 (Ki=17, 18, and 41 nM) [1].

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].

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.

Absorption, Distribution and Excretion
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. Perospirone is not reported to be accumulated after repeated dosing.
Perospirone is mainly excreted via renal elimination. 0.4% of of total dose is excreted as unchanged drug following oral administration of 8mg perospirone.
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.
Apparent clearance rate is approximately 425.5 ± 150.3 L/h in patients receiving a single oral dose of 8mg perospirone.

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Metabolism / Metabolites
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.
Perospirone has known human metabolites that include 4,5,6,7-Tetrahydro-2-[4-[4-(1,2-benzisothiazole-3-yl)piperazino]butyl]-2H-isoindole-1,3-dione, (3As,7aS)-2-[4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl]-7a-hydroxy-4,5,6,7-tetrahydro-3aH-isoindole-1,3-dione, 3-(1-Piperazinyl)-1,2-benzisothiazole, (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
The elimination half life is approximately 1.9 hours following oral ingestion of 8mg perospirone.

Protein Binding
Plasma protein binding ratio is 92% with extensive binding to serum albumin and α1-acid glycoprotein.

[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 a N-arylpiperazine.
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. Dainippon Sumitomo Pharma developed perospirone in Japan in 2001 for the treatment of acute schizophrenia and bipolar mania as well as chronic schizophrenia. 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. It is also shown to be less associated with extrapyramidal symptoms as a side effect compared to [DB00502].

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

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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. 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. 5-HT1A receptor activation further inhibits the release of 5-HT into the synaptic cleft.

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Pharmacodynamics
Perospirone is a serotonin 5-HT2 receptor inverse agonist and dopamine D2 receptor antagonist based on receptor binding experiments 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. 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.

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.)