ITI-722 (Lumateperone)

5-HT2A receptor (Ki = 0.54 nM)

Lumateperone (2-30 μM) 具有抗肿瘤活性，并能以剂量依赖性方式抑制细胞增殖[1]。细胞增殖实验[1] 细胞系：RPMI-8226细胞 浓度：2-30 μM 孵育时间：48小时 结果：抑制细胞生长，IC50值为17.30 μM。

Lumateperone（腹腔注射，1-10 mg/kg）以多巴胺 D1 受体依赖性方式促进 NMDA 和 AMPA 诱导的电流，并增加大鼠 mPFC 切片中多巴胺和谷氨酸的释放 [2]。动物模型：成年雄性Sprague-Dawley大鼠[2] 剂量：1-10 mg/kg 给药方式：腹腔注射 结果：1、3和10 mg/kg浓度20分钟后回避反应受到抑制。促进 NMDA 和 AMPA 敏感电流，还显着增加大鼠 mPFC 视锥细胞中 10 mg/kg 的多巴胺和谷氨酸释放。

Lumateperone能够渗透多药耐药蛋白1（MDR1），并且在7.4的pH下是非常亲脂性的，这是允许抗精神病药物在小肠和血脑屏障中被吸收的特征。Tmax发生在口服给药后3-4小时

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Lumateperone被广泛代谢。羰基侧链被酮还原酶还原，产生初级活性代谢产物。细胞色素P4503A4酶将lumateperone代谢为2种代谢产物：活性N-去甲基羰基代谢产物（IC200161）或N-去甲基醇代谢产物（IC 200565）。

Adult male Sprague-Dawley rats
1-10 mg/kg
Intraperitoneal injection

Absorption, Distribution and Excretion
Lumateperone is able to permeate multidrug resistance protein 1 (MDR1) and is very lipophilic at a pH of 7.4, which are characteristics that allow the antipsychotic to be absorbed in the small intestine and the blood brain barrier. Tmax occurs 3-4 hours after oral administration.
Due to it's molecular weight, virtually all unchanged lumateperone is excreted in the feces. Lumateperone's metabolites are very water soluble which is a property that allows for complete elimination. Approximately 58% of a lumateperone dose can be recovered in the urine, while 29% can be recovered in the feces.
The volume of distribution of lumateperone is approximately 4.1 L/Kg after intravenous administration.
Lumateperone's clearance is estimated to be 27.9 L/hour.

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Metabolism / Metabolites
Lumateperone is extensively metabolized. The carbonyl side chain is reduced by ketone reductase to produce the primary active metabolite. Cytochrome P450 3A4 enzymes metabolize lumateperone to 2 metabolites: the active N-desmethylated carbonyl metabolite (IC200161) or the N-desmethylated alcohol metabolite (IC200565).

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Biological Half-Life
Lumateperone's half life is reported to be between 13 to 18 hours. The reported half lives of the metabolites ICI200161 and ICI200131, are 20 and 21 hours respectively.

Hepatotoxicity
In preregistration controlled trials, ALT elevations arose in 2% of patients receiving lumateperone compared to less than 1% of placebo controls. The elevations, however, were usually mild, transient and typically resolved without dose modification or drug discontinuation. In preregistration trials, there were no instances of severe hepatic adverse events, discontinuations because of liver related events or episodes of clinically apparent liver injury with jaundice. Since its approval and more widescale use, there have been no published reports of liver injury with symptoms or jaundice attributed to lumateperone therapy, but clinical experience with its use has been limited.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of lumateperone during breastfeeding. However, amounts of lumateperone and its metabolites in breastmilk appear to be low and would not be expected to cause any adverse effects in breastfed infants. If lumateperone is required by the mother, it is not a reason to discontinue breastfeeding
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Lumateperone is approximately 97.4% plasma protein bound.

[1]. Identification of Trovafloxacin, Ozanimod, and Ozenoxacin as Potent c-Myc G-quadruplex Stabilizers to Suppress c-Myc Transcription and Myeloma Growth. Mol Inform. 2022 Mar 30:e2200011.

[2]. Lumateperone-mediated effects on prefrontal glutamatergic receptor-mediated neurotransmission: A dopamine D1 receptor dependent mechanism. Eur Neuropsychopharmacol. 2022 Jul 22;62:22-35.

[3]. Lumateperone (https://en.wikipedia.org/wiki/Lumateperone).

Schizophrenia is a complex mental illness and impacts approximately 1% of the population. Although there are several antipsychotics including [aripiprazole], [paliperidone] and [clozapine] available for clinical use, they are generally accompanied by significant metabolic and/or neurological adverse effects. Lumateperone is a newly approved 2nd generation antipsychotic currently indicated for the treatment of schizophrenia. It has a unique receptor binding profile and differs from other antipsychotics in that it modulates glutamate, serotonin and dopamine, which are all neurotransmitters that contribute to the pathophysiology of schizophrenia. The data so far indicates that lumateperone can alleviate both positive and negative symptoms of schizophrenia. Further, not only is the new antipsychotic selective for dopamine (D2) receptors in the mesolimbic and mesocortical brain regions, but it also has minimal off-target activity. Both characteristics lend to a more favourable adverse effect profile and ultimately safer drug.
Lumateperone is an Atypical Antipsychotic.
Lumateperone is a second generation (atypical) antipsychotic agent that is used in the treatment of schizophrenia. Lumateperone is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury.
See also: Lumateperone Tosylate (is active moiety of).

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Drug Indication
Lumateperone is approved for the treatment of schizophrenia in adults. It is also approved for the treatment of depressive episodes associated with bipolar disorder (i.e. bipolar depression) in adults, as monotherapy and/or adjunctive therapy with lithium or valproate.

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Mechanism of Action
There is much to learn about the pathophysiology of schizophrenia; however, dopamine abnormalities, specifically in the prefrontal and mesolimbic brain regions, are consistent in people with schizophrenia. In addition to dopamine, other neurotransmitters such as serotonin, glutamate, GABA and acetylcholine are thought to play a role. Lumateperone is unique among second generation antipsychotics based on its target profile and dopamine D2 receptor occupancy. Unlike other antipsychotics, lumateperone has partial agonist activity at presynaptic dopamine (D2) receptors, resulting in reduced presynaptic release of dopamine, and antagonistic activity at postsynaptic dopamine (D2) receptors. These characteristics allow lumateperone to efficiently reduce dopamine signaling. Lumateperone also targets dopamine (D1) receptors, and a useful secondary result of D1 activation is increased glutamatergic N-methyl-D-aspartate (NMDA) GluN2B receptor phosphorylation. This is significant since NMDA mediated glutamate signaling appears to be impaired in patients who have schizophrenia. Finally, lumateperone is capable of modulating serotonin by inhibiting serotonin transporters (SERT), and by behaving as a 5-HT2A receptor antagonist.

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Pharmacodynamics
Lumateperone, also known as ITI-007, is an atypical antipsychotic that has proven to be effective in the treatment of schizophrenia. Lumateperone's receptor binding profile is unique, allowing it to target schizophrenia related symptoms while minimizing adverse effects. In contrast to other second generation antipsychotics such as [lurasidone] and [brexpiprazole], lumateperone behaves as a partial agonist and as an antagonist at pre and postynaptic dopamine (D2) receptors respectively. Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) tend to have higher plasma concentrations of lumateperone than those with normal hepatic function. For this reason, patients with moderate or severe hepatic impairment should receive half the recommended daily dosage.

C24H28FN3O

393.497

393.221

C, 73.26; H, 7.17; F, 4.83; N, 10.68; O, 4.07

313368-91-1

Lumateperone tosylate; 1187020-80-9; 313368-91-1

21302490

Colorless to light yellow ointment

1.3±0.0 g/cm3

556.4±0.0 °C at 760 mmHg

290.3±0.0 °C

0.0±0.0 mmHg at 25°C

1.646

3.39

26.8Ų

0

5

5

29

593

2

FC1=CC=C(C(CCCN2CC[C@H]3[C@H](C4=CC=CC5=C4N3CCN5C)C2)=O)C=C1

HOIIHACBCFLJET-SFTDATJTSA-N

InChI=1S/C24H28FN3O/c1-26-14-15-28-21-11-13-27(16-20(21)19-4-2-5-22(26)24(19)28)12-3-6-23(29)17-7-9-18(25)10-8-17/h2,4-5,7-10,20-21H,3,6,11-16H2,1H3/t20-,21-/m0/s1

1-(4-fluorophenyl)-4-[(10R,15S)-4-methyl-1,4,12-triazatetracyclo[7.6.1.05,16.010,15]hexadeca-5,7,9(16)-trien-12-yl]butan-1-one

ITI 722; ITI007; ITI722; ITI007; ITI-007; ITI-722

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: ~79 mg/mL (~200.8 mM)
Ethanol: ~79 mg/mL

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;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。