Major metabolite of Quetiapine
Quetiapine sulfoxide acts as an antagonist at multiple neurotransmitter receptors, including serotonin 5-HT2A, dopamine D2, histamine H1, and adrenergic α1 and α2 receptors. It has relatively higher affinity for 5-HT2A receptors compared to D2 receptors, which is characteristic of atypical antipsychotics. It also has moderate affinity for muscarinic M1 receptors. The sulfoxide metabolite contributes to the receptor binding profile of quetiapine.

In vitro, quetiapine sulfoxide binds to and antagonizes serotonin 5-HT2A, dopamine D2, histamine H1, and adrenergic α1 and α2 receptors. It inhibits receptor-mediated signaling pathways. It has been studied in cell lines expressing these receptors to determine its binding affinity and functional activity. It may also have effects on neurotransmitter release and reuptake.

The estimated Cmax value of quetiapine sulfoxide is 77.3 ± 32.4 ng/mL (mean ± SD). For quetiapine sulfoxide, the calculated AUClast value is 1,286±458 ng·h/mL. The metabolic rate for quetiapine sulfoxide falls with time, averaging 30% after 72 hours following dosage compared to an average of 119% within 2 hours [1].
In vivo, quetiapine sulfoxide contributes to the antipsychotic, sedative, and antidepressant effects of quetiapine. It is present in the plasma of patients taking quetiapine and crosses the blood-brain barrier. Its receptor binding profile contributes to the therapeutic effects in schizophrenia and bipolar disorder, as well as side effects such as sedation, orthostatic hypotension, and weight gain.

For non-cellular enzyme/receptor binding assays, radioligand binding assays are used to assess affinity for serotonin 5-HT2A, dopamine D2, histamine H1, and adrenergic receptors. Competitive binding experiments using [3H]ketanserin (5-HT2A), [3H]spiperone (D2), [3H]mepyramine (H1), and [3H]prazosin (α1) are performed. Ki values are determined.

For in vitro cell-based assays, cells expressing the target receptors are cultured and treated with quetiapine sulfoxide. Receptor antagonism is measured by inhibition of agonist-induced signaling, such as calcium mobilization or cAMP accumulation. Cell viability and proliferation can be assessed using standard assays.

For in vivo studies, quetiapine sulfoxide is administered to animal models. Behavioral assays for antipsychotic activity (e.g., conditioned avoidance response, PCP-induced hyperactivity) can be used. Receptor occupancy studies can be performed to assess brain penetration and target engagement. Pharmacokinetic studies measure plasma and brain concentrations.

Pharmacokinetic properties include solubility in DMSO and water. It is a metabolite of quetiapine and is formed primarily by CYP3A4. It has a longer half-life than the parent drug. It is highly protein-bound and extensively metabolized. Storage is typically at -20°C. It is a solid and should be handled with standard laboratory precautions.

As a metabolite of quetiapine, its safety profile is similar to the parent drug. It can cause sedation, orthostatic hypotension, weight gain, and metabolic effects. It is not for human use in research settings without appropriate approval.

[1]. Comparison of Capillary and Venous Drug Concentrations After Administration of a Single Dose of Risperidone, Paliperidone, Quetiapine, Olanzapine, or Aripiprazole. Clin Pharmacol Drug Dev. 2016 Nov;5(6):528-537.

[2]. Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models. Br J Pharmacol. 2016 Jan;173(1):155-66.

Background and Objectives: Quetiapine possesses a different range of clinical activity than other atypical antipsychotics, and its monotherapy is effective against bipolar depression, major depressive disorder, and generalized anxiety disorder. Although the neuropharmacological mechanisms underlying its clinical efficacy are not fully elucidated, its main active metabolite, norquetiapine, has been shown to possess unique in vitro pharmacological characteristics consistent with its broad therapeutic range and may contribute to the clinical efficacy of quetiapine. Methods: We used in vitro binding and functional analyses to evaluate the binding and function of quetiapine and norquetiapine to known targets of action of antidepressants and anxiolytics, and compared these activities with a range of representative marketed antipsychotics and antidepressants. To determine how in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to the effects of marketed antidepressant-like and anxiolytic-like drugs. Main Results: Norquetiapine exhibited activity at the norepinephrine transporter (NET) comparable to known antidepressants, while quetiapine itself showed no activity. Norquetiapine showed activity in both the forced swimming test in mice and the learned helplessness test in rats. In vivo receptor occupancy studies showed that norquetiapine had a significant occupancy of NET at behaviorally relevant doses. Both quetiapine and norquetiapine are 5-HT1A receptor agonists, and the anxiolytic-like activity of norquetiapine in the punishment response in rats can be blocked by the 5-HT1A receptor antagonist WAY100635. Conclusion and significance: Quetiapine and norquetiapine have a variety of in vitro pharmacological effects. Preclinical studies have shown that their activity on NET and 5-HT1A receptors helps quetiapine exert antidepressant and anxiolytic effects in patients. [1] Risperidone, paliperidone, quetiapine, olanzapine and aripiprazole are approved antipsychotic drugs for the treatment of a variety of mental disorders, including schizophrenia. This randomized, parallel-group, open-label study aimed to compare the concentrations of the above drugs in fingertip capillary blood, whole venous blood and plasma in healthy volunteers after a single dose of the above drugs. All whole blood and plasma drug concentrations were determined using a validated liquid chromatography-tandem mass spectrometry method. Drug concentrations in capillary and venous blood (including plasma and whole blood) were generally consistent, but time-dependent differences were observed, particularly with olanzapine and paliperidone, with capillary blood drug concentrations being slightly higher than venous blood drug concentrations in the first few hours after a single dose. Given the wide range of therapeutic concentrations and the broad range of drug concentrations in the patient population for a given dose, the observed differences between capillary and venous plasma drug concentrations are not expected to be significant in clinical practice. Based on these results, capillary drug concentrations from finger-prick blood have been shown to approximate venous drug concentrations. [2]
Quetiapine sulfoxide dihydrochloride is an active metabolite of quetiapine, an atypical antipsychotic used to treat schizophrenia, bipolar disorder, and major depressive disorder. It acts as an antagonist at serotonin 5-HT2A and dopamine D2 receptors, contributing to the therapeutic effects of quetiapine. It is primarily formed by CYP3A4 metabolism.

C21H27CL2N3O3S

472.428382158279

471.115

329218-11-3

Quetiapine;111974-69-7;Quetiapine hemifumarate;111974-72-2;Quetiapine sulfoxide;329216-63-9;Quetiapine sulfoxide hydrochloride;2448341-72-6

45358163

White to yellow solid powder

3.652

3

7

6

30

515

0

MPRQQJUQOLNAFP-UHFFFAOYSA-N

InChI=1S/C21H25N3O3S.2ClH/c25-14-16-27-15-13-23-9-11-24(12-10-23)21-17-5-1-3-7-19(17)28(26)20-8-4-2-6-18(20)22-21;;/h1-8,25H,9-16H2;2*1H

2-[2-[4-(11-oxobenzo[b][1,4]benzothiazepin-6-yl)piperazin-1-yl]ethoxy]ethanol;dihydrochloride

329218-11-3; Quetiapine sulfoxide (dihydrochloride); Quetiapine Sulfoxide Dihydrochloride; Ethanol, 2-[2-[4-(5-oxidodibenzo[b,f][1,4]thiazepin-11-yl)-1-piperazinyl]ethoxy]- ,dihydrochloride; Quetiapine S-oxide dihydrochloride; 2-[2-[4-(11-oxobenzo[b][1,4]benzothiazepin-6-yl)piperazin-1-yl]ethoxy]ethanol;dihydrochloride; ETHANOL,2-[2-[4-(5-OXIDODIBENZO[B,F][1,4]THIAZEPIN-11-YL)-1-PIPERAZINYL]ETHOXY]-,DIHYDROCHLORIDE;

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)

H2O : ~250 mg/mL (~529.18 mM)

Solubility in Formulation 1: 50 mg/mL (105.84 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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