Methotrimeprazine acts primarily as an antagonist at dopamine D2 receptors in the brain, which is largely responsible for its antipsychotic effect. It also binds to serotonin 5-HT2 receptors, which may contribute to its therapeutic effects. Additionally, it blocks histamine H1 receptors (contributing to sedation), adrenergic receptors (contributing to hypotensive effects), and has inhibitory effects on the SERCA pump, inducing an increase in cytoplasmic Ca2+ levels. Its broad receptor binding profile accounts for its diverse clinical applications and side effect profile.

In vitro, methotrimeprazine demonstrates activity at multiple receptor targets, including dopamine D2, serotonin 5-HT2, histamine H1, and adrenergic receptors. It inhibits the SERCA pump and induces an increase in cytoplasmic calcium levels in cell-based assays. Its antipsychotic activity has been characterized in receptor binding and functional assays, showing potent antagonism at dopamine receptors. The compound also exhibits antiviral, anti-inflammatory, neuroprotective, analgesic, and anti-nociceptive activities in various in vitro models.

In vivo, methotrimeprazine is effective in managing psychotic symptoms, with clinical use in schizophrenia and bipolar disorder. Its potent sedative effects make it valuable in palliative care for managing severe agitation and distress. As a Ca2+ release inducer, it has been studied for its broader pharmacological effects. The compound’s in vivo efficacy is well-established in clinical practice, with dose-dependent therapeutic effects and a side effect profile consistent with its receptor pharmacology.

In vitro enzyme/receptor binding studies for methotrimeprazine typically involve radioligand binding assays using membrane preparations from tissues or cells expressing dopamine D2, serotonin 5-HT2, histamine H1, or adrenergic receptors. Competitive binding experiments with labeled ligands such as [3H]-spiperone (for D2) or [3H]-ketanserin (for 5-HT2) are performed to determine affinity (Ki) values. Standard protocols involve incubating membranes with increasing concentrations of methotrimeprazine in the presence of a fixed concentration of radioligand, followed by filtration and scintillation counting. SERCA pump inhibition can be assessed using ATPase activity assays.

In vitro cellular assays for methotrimeprazine include studies using cell lines expressing dopamine or serotonin receptors to measure receptor-mediated signaling. Common assays measure calcium mobilization using fluorescent indicators (for Gq-coupled receptors) or cAMP accumulation (for Gi-coupled receptors). For SERCA pump inhibition, cells are treated with the compound and cytoplasmic Ca2+ levels are measured using fluorescent dyes such as Fura-2. Cytotoxicity and cell viability are assessed using standard MTT or resazurin assays to determine the compound’s safety profile.

In vivo animal studies for methotrimeprazine include behavioral pharmacology models to assess antipsychotic activity, such as amphetamine-induced hyperactivity or conditioned avoidance response in rodents. Analgesic activity is evaluated in pain models such as the hot plate or tail-flick tests. The compound’s sedative effects are assessed in locomotor activity tests. Standard protocols involve administration via oral, intraperitoneal, or subcutaneous routes, with dose-response relationships and comparison to reference antipsychotic agents. Toxicity and side effects are also monitored in these studies.

Absorption, Distribution and Excretion
Methoxypromethazine has incomplete oral bioavailability due to significant first-pass metabolism in the liver. Oral bioavailability is approximately 50% to 60%. Metabolism/Metabolites Hepatic Metabolism Methoxypromethazine is metabolized in the liver and degraded into sulfoxides, glucuronic acid, and a demethylated moiety. Hepatic Metabolism Methoxypromethazine is metabolized in the liver and degraded into sulfoxides, glucuronic acid, and a demethylated moiety. Half-life: Approximately 20 hours. Biological Half-life Approximately 20 hours.
Pharmacokinetic properties of methotrimeprazine include good oral bioavailability, with peak plasma concentrations achieved within a few hours of administration. It is extensively metabolized in the liver, primarily via demethylation and hydroxylation, and its metabolites are excreted renally. The compound has a moderate half-life, supporting multiple daily dosing in clinical practice. Its distribution includes penetration into the central nervous system, which is essential for its antipsychotic effects. Protein binding is high, and the drug accumulates in tissues with prolonged use.

Toxicity Summary
The antipsychotic effects of methoxypromethazine are primarily attributed to its antagonistic effect on dopamine receptors in the brain. Additionally, its binding to 5-HT2 receptors may also play a role. Methoxypromethazine exerts its effects by blocking central adrenergic, dopamine, serotonin, and anticholinergic pathways.
Toxicological data for methotrimeprazine include significant side effects related to its receptor pharmacology, including sedation, hypotension, anticholinergic effects (dry mouth, constipation, blurred vision), extrapyramidal symptoms (due to dopamine D2 antagonism), and weight gain. It may cause QT prolongation and should be used with caution in patients with cardiac conditions. Overdose can cause severe central nervous system depression, coma, and respiratory depression. Long-term use requires monitoring for tardive dyskinesia and metabolic syndrome. Contraindications include severe cardiovascular disease, coma, and known hypersensitivity.

[1]. Levomepromazine for nausea and vomiting in palliative care. Cochrane Database Syst Rev. 2015 Nov 2;(11):CD009420.

[2]. Levomepromazine for schizophrenia. Cochrane Database Syst Rev. 2010 Oct 6;(10):CD007779.

Methotrimeprazine is a phenothiazine compound with the structure 10H-phenothiazine, substituted at positions 10 and 2 with (2R)-3-(dimethylamino)-2-methylpropyl and methoxy, respectively. It possesses a variety of pharmacological activities, including as a phenothiazine antipsychotic, dopaminergic antagonist, serotonergic antagonist, cholinergic antagonist, non-narcotic analgesic, EC 3.4.21.26 (prolyl oligopeptidase) inhibitor, and anticoronavirus drug. It belongs to the phenothiazine class of compounds and is also a tertiary amine. It is a 10H-phenothiazine hydride derivative. Methotrimeprazine is a phenothiazine compound with pharmacological activities similar to chlorpromazine and promethazine. It possesses the histamine antagonistic properties of antihistamines while also producing effects on the central nervous system similar to chlorpromazine. (Excerpt from Martindale Pharmacopoeia, 30th Edition, p. 604)
Levopromethazine is a phenothiazine drug and a typical antipsychotic with sedative/hypnotic, anti-anxiety, antiemetic, analgesic, and antipsychotic effects. Although the exact mechanism of action of levopromethazine is not fully understood, after administration, it appears to antagonize multiple receptors in the central nervous system (CNS), including adrenergic receptors, dopamine receptors, histamine receptors, cholinergic receptors, and serotonin (5-hydroxytryptamine; 5-HT) receptors. Blocking these receptors is what allows levopromethazine to exert its pharmacological effects.
Methoxypromethazine is only found in individuals who have used or taken this drug. It is a phenothiazine drug with pharmacological activity similar to chlorpromazine and promethazine. It has the histamine-antagonistic properties of an antihistamine and CNS effects similar to chlorpromazine. (Excerpt from Martindale Pharmacopoeia, 30th Edition, p. 604) The antipsychotic effect of methoxypromethazine is primarily attributed to its antagonistic effect on dopamine receptors in the brain. Additionally, its binding to 5-HT2 receptors may also play a role. It is a phenothiazine drug with pharmacological activity similar to chlorpromazine and promethazine. It possesses the histamine-antagonistic properties of antihistamines while having similar effects on the central nervous system as chlorpromazine. (From Martindale Pharmacopoeia, 30th edition, p. 604) See also: Phenothiazines (subclasses). Indications: Used for the treatment of psychosis, particularly the manic phase of schizophrenia and bipolar disorder. Mechanism of Action: The antipsychotic effect of methoxypromethazine is primarily attributed to its antagonistic effect on dopamine receptors in the brain. Additionally, its binding to 5-HT2 receptors may also play a role. Pharmacodynamics: Methoxypromethazine is a phenothiazine drug with pharmacological activity similar to chlorpromazine and promethazine. It possesses the histamine-antagonistic properties of antihistamines, while also producing effects on the central nervous system similar to chlorpromazine. (Excerpt from Martindale Pharmacopoeia, 30th edition, page 604)
Methotrimeprazine is approved in many countries for the treatment of psychosis and is also used off-label for pain management and palliative care. It is known by the brand name Nozinan. Its broad pharmacological profile makes it a versatile agent in psychiatric and palliative settings. It is available as tablets and injectable formulations. The compound’s combination of antipsychotic, analgesic, and sedative properties makes it particularly useful for managing terminal illness and severe psychiatric conditions. It remains an important agent in psychopharmacology and palliative medicine.

C19H24N2OS

328.47

328.161

C, 69.47; H, 7.36; N, 8.53; O, 4.87; S, 9.76

60-99-1

7104-38-3; 1236-99-3 (HCl); 60-99-1

72287

White to off-white solid powder

1.125g/cm3

468ºC at 760 mmHg

117°C

236.8ºC

1.594

4.56

0

4

5

23

378

1

C[C@H](CN(C)C)CN1C2=CC=CC=C2SC3=C1C=C(C=C3)OC

VRQVVMDWGGWHTJ-CQSZACIVSA-N

InChI=1S/C19H24N2OS/c1-14(12-20(2)3)13-21-16-7-5-6-8-18(16)23-19-10-9-15(22-4)11-17(19)21/h5-11,14H,12-13H2,1-4H3/t14-/m1/s1

(2R)-3-(2-methoxyphenothiazin-10-yl)-N,N,2-trimethylpropan-1-amine

Nozinan; Nosinan; Levomepromazine; Methoxytrimeprazine; mepromazine; Methotrimeprazine; Milezin; Minozinan; Neozine

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: ~41.7 mg/mL (~126.9 mM)

Solubility in Formulation 1: ≥ 1.43 mg/mL (4.35 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 14.3 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: ≥ 1.43 mg/mL (4.35 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 14.3 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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Solubility in Formulation 3: ≥ 1.43 mg/mL (4.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 14.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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