Piperospirone（SM-9018 游离碱）对 α1、5-HT1 和 D1 表现出显着的亲和力（Ki=17、18 和 41 nM）[1]。

Perospirone（SM-9018 游离碱；1.0-10.0 mg/kg/天；紊乱；持续 14 天）可显着且剂量依赖性地减少 PCP 引起的认知异常 [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

84.99

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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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