5-HT_2A Receptor ( Ki = 0.54 nM )
Lumateperone tosylate (2-30 μM) exhibits anti-tumor activity and has the ability to dose-dependently inhibit cell proliferation[1].

Lumateperone tosylate (2-30 μM) exhibits anti-tumor activity and has the ability to dose-dependently inhibit cell proliferation[1].

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Using intracellular recording in vitro in layer V/VI pyramidal cells of the rat medial prefrontal cortex (mPFC), Lumateperone (30 nM) significantly facilitated both NMDA- and AMPA-induced currents. The maximal effect was a 150.7 ± 15.7% increase in NMDA-induced currents and a 138.8 ± 10.0% increase in AMPA-induced currents compared to control. This facilitation showed an inverted U-shaped concentration-response relationship and was dependent on dopamine D1 receptor activation, as it was prevented by pretreatment with the D1 antagonist SCH23390 (1 µM). [2]

Lumateperone (i.p., 1-10 mg/kg) tosylate stimulates the release of dopamine and glutamate in rat mPFC slices and promotes NMDA and AMPA-induced currents in a manner that is dependent on the dopamine D 1 receptor[2].

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In the conditioned avoidance response (CAR) test in rats, systemic administration of Lumateperone (3 and 10 mg/kg, i.p.) significantly suppressed avoidance response 20 minutes post-injection, indicating an antipsychotic-like effect. No escape failures were observed, suggesting a low risk of nonspecific side effects. The effect was transient, with behavior returning to baseline by 90 minutes post-injection. [2]
Using in vivo microdialysis in the rat mPFC, Lumateperone (10 mg/kg, i.p.) caused a robust, rapid, and sustained elevation of extracellular dopamine levels. Lower doses (1 and 3 mg/kg) did not produce a significant increase. [2]
Using in vivo amperometry in the rat mPFC, Lumateperone (10 mg/kg, i.p.) significantly increased extracellular glutamate release, starting approximately 15 minutes after administration and plateauing around 50 minutes post-injection. The increase was sustained for the duration of the 120-minute recording period. [2]

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.

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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).

Cell Line: RPMI-8226 cells
Concentration: 2-30 μM
Result: Inhibited cell growth with the IC50 value of 17.30 μM.

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

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Conditioned Avoidance Response (CAR) Test: Adult male Sprague-Dawley rats were trained in shuttle boxes. After achieving stable avoidance performance (≥85%), they received intraperitoneal (i.p.) injections of Lumateperone (1, 3, or 10 mg/kg) or vehicle. Behavioral testing sessions (10 min) were conducted 20, 90, and 240 minutes post-injection. Avoidances, escapes, and escape failures were recorded. [2]
Ex Vivo Brain Slice Electrophysiology: Brain slices containing the mPFC were prepared from male Sprague-Dawley rats. Pyramidal neurons in layers V/VI were recorded using standard intracellular techniques under voltage-clamp. NMDA (10-15 µM) or AMPA (1.5-2.5 µM) was applied via bath perfusion to induce currents. After establishing control responses, Lumateperone (concentrations ranging from 3 to 100 nM) was bath-applied, and its effect on agonist-induced currents was measured 5 and 30 minutes later. In some experiments, slices were pretreated with the D1 antagonist SCH23390 (1 µM) or phencyclidine (PCP, 1 µM) before Lumateperone application. [2]
In Vivo Microdialysis: Male Wistar Han rats were implanted with custom-made microdialysis probes targeted at the mPFC. After 48 hours of recovery, probes were perfused with Ringer's solution. After establishing a stable baseline of extracellular dopamine (3 consecutive stable samples), rats received an i.p. injection of Lumateperone (1, 3, or 10 mg/kg) or vehicle. Dialysate samples were collected every 30 minutes for 270 minutes post-injection and analyzed for dopamine content by HPLC with electrochemical detection. [2]
In Vivo Amperometry: Male Sprague-Dawley rats were implanted under anesthesia with a ceramic microelectrode array (MEA) coated with glutamate oxidase, targeted at the mPFC. After surgical implantation and system stabilization (≥60 min), rats received an i.p. injection of Lumateperone (10 mg/kg) or vehicle. Extracellular glutamate levels were recorded via amperometry at a frequency of 10 Hz for at least 120 minutes post-injection. The electrodes were calibrated in vitro prior to implantation against known concentrations of glutamate, ascorbic acid, dopamine, and H2O2. [2]

In CAR testing, administration of doses up to 10 mg/kg of Lumateperone did not result in escape failure, indicating that at these doses, Lumateperone does not cause dyskinesia or sedation in this model. [2]
This article cites previous studies that have shown that doses up to 10 mg/kg of Lumateperone do not cause forelimb rigidity in mice, suggesting a low risk of extrapyramidal side effects. [2]

[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.

Pharmacodynamics
Lumateperone, also known as ITI-007, is an atypical antipsychotic drug that has been proven effective in treating schizophrenia. Lumateperone possesses unique receptor-binding properties, allowing it to target schizophrenia-related symptoms while minimizing adverse reactions. Unlike other second-generation antipsychotics such as lurasidone and birepiperazole, lumateperone acts as a partial agonist and antagonist of presynaptic and postsynaptic dopamine (D2) receptors, respectively. Plasma concentrations of lumateperone are often higher in patients with moderate or severe hepatic impairment (Child-Pugh B or C) than in patients with normal hepatic function. Therefore, patients with moderate or severe hepatic impairment should take half the recommended daily dose.

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Biological Half-Life
The half-life of lumateperone has been reported to be 13 to 18 hours. The half-lives of the metabolites ICI200161 and ICI200131 are reported to be 20 hours and 21 hours, respectively.

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Mechanism of Action
There is still much to be learned about the pathophysiology of schizophrenia; however, dopamine abnormalities are prevalent in schizophrenic patients, particularly in the prefrontal cortex and mesolimbic region. Besides dopamine, other neurotransmitters such as serotonin, glutamate, gamma-aminobutyric acid (GABA), and acetylcholine are also believed to play a role. Rumatepirozon stands out among second-generation antipsychotics due to its target spectrum and dopamine D2 receptor occupancy. Unlike other antipsychotics, rumatepirozon has partial agonist activity against presynaptic dopamine (D2) receptors, thereby reducing presynaptic dopamine release, and also has antagonistic effects on postsynaptic dopamine (D2) receptors. These properties enable rumatepirozon to effectively reduce dopamine signaling. Rumatepirozon also targets the dopamine (D1) receptor, and a beneficial secondary consequence of D1 receptor activation is increased phosphorylation of the glutamatergic N-methyl-D-aspartate (NMDA)GluN2B receptor. This is significant because NMDA-mediated glutamate signaling appears to be impaired in patients with schizophrenia. Finally, rumatepirozon is able to modulate serotonin by inhibiting the serotonin transporter (SERT) and acting as a 5-HT2A receptor antagonist.

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Hepatotoxicity
In the pre-registration controlled trial, 2% of patients treated with rumatepirozon experienced elevated ALT levels, compared to less than 1% in the placebo control group. However, these elevations were generally mild, transient, and usually resolved without dose adjustment or discontinuation. No serious hepatic adverse events, discontinuation due to hepatic events, or clinically significant liver injury with jaundice occurred in the pre-registration trial. Since its approval and wider use, there have been no published reports of liver injury with symptoms or jaundice caused by lumateperone treatment, but its clinical experience is limited. Likelihood score: E (unlikely to be the cause of clinically significant liver injury). Lumateperone is an FDA-approved drug for the treatment of schizophrenia in adults and depressive episodes associated with type I or II bipolar disorder (as monotherapy or adjunctive therapy). [2] It has a novel multimodal mechanism of action that simultaneously modulates the neurotransmission of serotonin, dopamine and glutamate. [2] Lumateperone promotes the function of prefrontal NMDA/AMPA receptors and increases dopamine/glutamate release through a D1 receptor-dependent mechanism, which may be the basis for its clinical efficacy in improving not only positive symptoms of schizophrenia and bipolar disorder, but also negative symptoms, depressive symptoms and associated cognitive deficits. [2] Clinical trials have shown that lumateperone has a good safety profile with a low risk of extrapyramidal symptoms, metabolic side effects and elevated prolactin levels. [2]

C24H28FN3O-HCL

393.22

C, 65.82; H, 6.41; F, 3.36; N, 7.43; O, 11.31; S, 5.67

Lumateperone; 313368-91-1

44241743

White to gray solid powder

LHAPOGAFBLSJJQ-GUTACTQSSA-N

InChI=1S/C24H28FN3O.C7H8O3S/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;1-6-2-4-7(5-3-6)11(8,9)10/h2,4-5,7-10,20-21H,3,6,11-16H2,1H3;2-5H,1H3,(H,8,9,10)/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;4-methylbenzenesulfonic acid

ITI722; ITI-722; ITI 722; Lumateperone toluenesulfonic acid; Lumateperone PTSA salt; ITI-007; ITI 007; ITI007; Lumateperone, Caplyta; UNII:JIE88N006O; ITI-007 tosylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: ~100 mg/mL (~176.8 mM)
H2O: < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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