Fluphenazine

Synthetic Routes and Reaction Conditions: Fluphenazine is synthesized through a multi-step process. The synthesis begins with the preparation of 2-trifluoromethyl phenothiazine, which is achieved by decarboxylation and cyclization reactions starting from flufenamic acid. This intermediate is then reacted with 1-(2-ethoxyl)piperazine and 1,3-bromochloropropane to form 1-(3-chloropropyl)-4-(2-ethoxyl)piperazine. Finally, a condensation reaction between these intermediates yields this compound .

Industrial Production Methods: Industrial production of this compound involves similar synthetic routes but on a larger scale. The process is optimized for yield and purity, often involving high-performance liquid chromatography (HPLC) for quality control .

Types of Reactions: Fluphenazine undergoes various chemical reactions, including:

Oxidation: this compound can be oxidized under specific conditions, leading to the formation of degradation products.

Reduction: Reduction reactions can modify the functional groups in this compound, altering its pharmacological properties.

Substitution: Substitution reactions, particularly involving the trifluoromethyl group, can lead to the formation of different analogs

Common Reagents and Conditions:

Oxidation: Hydrogen peroxide or other oxidizing agents under controlled conditions.

Reduction: Reducing agents like lithium aluminum hydride.

Substitution: Halogenating agents for introducing or modifying halogen groups.

Major Products Formed: The major products formed from these reactions include various analogs and degradation products, which can be characterized using techniques like LC-MS/MS .

Pharmacological Mechanism

Fluphenazine operates by blocking postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain, which is crucial for its antipsychotic effects. Additionally, it depresses the release of hypothalamic and hypophyseal hormones and is believed to influence various physiological functions such as metabolism and wakefulness .

Schizophrenia Management

This compound is primarily indicated for the treatment of schizophrenia. Its long-acting injectable formulation, this compound decanoate, is particularly useful for patients who struggle with medication adherence. Studies indicate that this compound decanoate can reduce relapse rates compared to placebo treatments, although the quality of evidence supporting its efficacy remains low .

Long-Acting Injectable Formulations

This compound decanoate has been shown to produce fewer movement disorders compared to oral antipsychotics. A review of multiple studies suggests that while this compound decanoate is effective, the evidence quality is often rated low or very low due to methodological limitations in trials .

Off-Label Uses

This compound has also been used off-label for conditions such as chronic tic disorders and Huntington's disease. However, its use in these areas is less common and not FDA-approved, indicating a need for caution among clinicians .

Case Study: Treatment-Refractory Schizophrenia

A notable case involved a patient with treatment-refractory schizophrenia who was administered this compound decanoate alongside fluoxetine. The combination resulted in increased serum concentrations of this compound and minor improvements in symptoms despite initial challenges in achieving therapeutic levels . This case underscores the potential benefits of pharmacokinetic interactions in optimizing treatment.

Case Report: Bradycardia Induced by this compound Decanoate

Another significant case reported bradycardia as a side effect following administration of this compound decanoate. The patient exhibited a pulse rate drop to 46 beats per minute shortly after treatment initiation, highlighting the importance of cardiac monitoring when prescribing this medication .

Comparative Effectiveness

Comparative studies have evaluated this compound against other antipsychotics, revealing that while it remains effective, newer atypical antipsychotics are often preferred due to their improved side-effect profiles. This compound's efficacy is comparable to lower-potency agents like chlorpromazine but has seen decreased usage in favor of these newer alternatives .

Fluphenazine exerts its effects by blocking postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain. This action depresses the release of hypothalamic and hypophyseal hormones and affects the reticular activating system, influencing basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis .

Fluphenazine Enanthate vs. This compound Decanoate

Both esters are prodrugs of this compound, differing in pharmacokinetics due to ester chain length:

*EPS: Extrapyramidal symptoms. This compound decanoate is preferred clinically due to prolonged efficacy and reduced dosing frequency .

Other Phenothiazines: Chlorpromazine and Perphenazine

This compound shares structural similarities with chlorpromazine (a phenothiazine prototype) but differs in potency and side-effect profiles:

• Chlorpromazine : Lower D2 affinity, higher histaminergic and anticholinergic effects, leading to sedation but fewer extrapyramidal symptoms (EPS) .
• Perphenazine : Intermediate potency, with a higher risk of EPS compared to chlorpromazine but lower than this compound .

Non-Phenothiazine Antipsychotics

Haloperidol (Butyrophenone) :

• Comparable efficacy to this compound decanoate in schizophrenia .
• Higher risk of EPS but lower metabolic side effects .

Flupenthixol Decanoate (Thioxanthene) :

• In a double-blind trial, 40 mg flupenthixol decanoate ≈ 25 mg this compound decanoate in antipsychotic efficacy .
• Flupenthixol exhibits mood-elevating effects, whereas this compound may lower mood .

Fluspirilene (Diphenylbutylpiperidine) :

This compound Derivatives and Analogues

This compound-Mustard :

• Irreversible calmodulin antagonist with cytotoxic properties.
• Induces DNA strand breaks and shows antiproliferative effects in malignant cells at IC50 values <10 µM .

Repurposing in Oncology

This compound demonstrates anticancer activity via cholesterol disruption and autophagy induction:

This compound also reduces oxaliplatin-induced neuropathic pain in murine models, suggesting dual therapeutic benefits in cancer patients .

Key Research Findings

• Schizophrenia Management: this compound decanoate plasma levels correlate with reduced psychotic exacerbations (p = 0.003 at 9 months) .
• Neuroprotection : Enhances autophagy and reduces α1-antitrypsin aggregation in C. elegans and mammalian models .
• Safety Profile : Lower hepatotoxicity risk compared to chlorpromazine but associated with rare cholestatic liver injury .

Fluphenazine is a first-generation antipsychotic drug primarily used in the treatment of schizophrenia and other psychotic disorders. Beyond its established role in psychiatry, recent studies have highlighted its potential biological activities, particularly in oncology and neuropharmacology. This article explores the biological activity of this compound, focusing on its mechanisms of action, effects on cancer cells, and relevant case studies.

This compound exerts its effects mainly by antagonizing dopamine D2 receptors in the central nervous system (CNS), which leads to a reduction in dopaminergic activity. This mechanism is crucial for its antipsychotic properties but also contributes to various side effects, including extrapyramidal symptoms. Additionally, this compound has been identified as a calmodulin inhibitor, affecting calcium signaling pathways that are vital for numerous cellular processes, including cell proliferation and apoptosis .

Anticancer Activity

Recent research has illuminated this compound's potential as an anticancer agent. Studies have demonstrated that this compound can induce apoptosis in various cancer cell lines through several mechanisms:

• DNA Fragmentation : this compound has been shown to cause DNA damage in cancer cells, leading to programmed cell death.
• Cell Cycle Arrest : The compound induces G0/G1 phase arrest by downregulating cyclin-dependent kinases (CDKs) and upregulating cell cycle inhibitors such as p21 and p27 .
• Inhibition of Migration and Invasion : this compound decreases the migratory and invasive capabilities of cancer cells, potentially through modulation of signaling pathways like Akt and Wnt .

Table 1: Summary of this compound's Biological Activities

Research Findings

A comprehensive review highlighted this compound's ability to cross the blood-brain barrier effectively, with a concentration ratio indicating significant bioavailability in the brain . In vitro studies confirmed that low concentrations (under 15 µM) significantly reduced the viability of breast cancer cell lines (4T1 and MDA-MB-231) over time . Furthermore, this compound's apoptotic effects were corroborated by increased levels of cleaved caspases and altered expression of Bcl-2 family proteins.

Case Studies

• High-Dose this compound in Treatment-Resistant Patients :
  A study involving patients with severe character disorders treated with high doses (300 to 1200 mg/day) showed notable improvements in symptoms. However, side effects included sedation, which was more pronounced at higher doses .
• This compound Decanoate-Induced Bradycardia :
  A case report documented a patient experiencing bradycardia after receiving this compound decanoate. The patient's heart rate dropped to 46 bpm 36 hours post-administration, necessitating careful cardiac monitoring during treatment .
• Anticancer Efficacy Against Human Cancer Cells :
  In vitro studies demonstrated that this compound could inhibit the growth of various cancer cell lines, suggesting its potential utility as an adjunctive therapy in oncology .

Basic Research Questions

Q. What are the primary pharmacological mechanisms of fluphenazine, and how do they inform experimental design in preclinical studies?

this compound acts as a potent dopamine D2 receptor antagonist, with additional affinity for serotonin and adrenergic receptors. To study its mechanisms, preclinical experiments should employ dose-response assays (e.g., radioligand binding studies) to quantify receptor affinity (Kd values) and functional antagonism (e.g., cAMP inhibition assays). Include controls for off-target effects using selective receptor antagonists and validate findings with in vivo models (e.g., catalepsy tests in rodents). Ensure rigorous blinding and randomization to mitigate bias .

Q. How should researchers standardize this compound dosing in animal studies to ensure translational relevance?

Dosing must account for species-specific pharmacokinetics (e.g., metabolic clearance differences between rodents and primates). Use plasma concentration monitoring via HPLC or LC-MS to correlate administered doses with bioactive levels. Reference established ED50 values for behavioral endpoints (e.g., apomorphine-induced stereotypy suppression) and adjust for bioavailability. Document batch-to-batch variability in drug purity using NMR and mass spectrometry .

Q. What are the critical considerations for designing clinical trials comparing this compound to newer antipsychotics?

Prioritize double-blind, randomized controlled trials (RCTs) with active comparators (e.g., risperidone, olanzapine). Define primary endpoints (e.g., PANSS scores for symptom reduction) and secondary endpoints (e.g., extrapyramidal symptom incidence). Use stratified randomization to balance covariates like baseline symptom severity and prior treatment history. Power calculations should account for dropout rates, referencing historical attrition data from Cochrane reviews .

Advanced Research Questions

Q. How can researchers resolve contradictions in efficacy data between this compound and low-potency antipsychotics?

Conduct meta-analyses with subgroup analyses to identify moderators (e.g., patient age, comorbidities). For example, highlights conflicting results in sedation rates (this compound: 20% vs. low-potency: 64%, RR 0.31). Use mixed-effects models to adjust for study heterogeneity and publication bias. Share raw datasets via repositories adhering to FAIR principles (e.g., Figshare) to enable independent validation .

Q. What methodologies are optimal for studying this compound’s long-term neurobiological effects?

Longitudinal neuroimaging (e.g., fMRI or PET scans) paired with post-mortem histopathology can assess dopamine receptor upregulation and structural changes (e.g., volumetric reductions in the basal ganglia). Combine this with transcriptomic profiling (RNA-seq) of brain tissue to identify pathways affected by chronic exposure. Use propensity score matching in observational studies to control for confounders like concomitant medications .

Q. How should researchers address ethical challenges in trials involving this compound’s adverse effects?

Adhere to protocols for monitoring extrapyramidal symptoms (EPS) using validated scales (e.g., Simpson-Angus Scale). Implement stopping rules for severe adverse events (e.g., tardive dyskinesia) and ensure informed consent documents explicitly outline risks. For vulnerable populations (e.g., treatment-resistant schizophrenia), justify risk-benefit ratios using prior efficacy data and include independent data safety monitoring boards .

Q. What statistical approaches are recommended for analyzing this compound’s dose-response relationships in heterogeneous populations?

Use nonlinear mixed-effects modeling (NONMEM) to account for inter-individual variability. Incorporate covariates like CYP2D6 genotype (affecting metabolism) and body mass index. For sparse sampling, apply Bayesian hierarchical models to estimate population pharmacokinetics. Validate models with bootstrapping or cross-validation, reporting 95% confidence intervals for all parameters .

Q. Methodological Guidance

Q. How to ensure reproducibility in this compound synthesis and characterization studies?

Document synthetic routes using IUPAC nomenclature and report yields, purity (>95% by HPLC), and spectral data (1H/13C NMR, HRMS) in supplemental materials. For novel derivatives, provide crystallographic data (CCDC deposition numbers) and solubility profiles in biorelevant media (e.g., simulated gastric fluid). Use open-source software (e.g., ChemAxon) for structure verification .

Q. What frameworks are effective for formulating hypothesis-driven research questions on this compound?

Apply the PICO framework:

• Population : Patients with acute psychosis (DSM-5 criteria).
• Intervention : this compound decanoate (long-acting injectable).
• Comparison : Oral this compound hydrochloride.
• Outcome : Relapse rates over 6 months. Evaluate feasibility using FINER criteria (Feasible, Interesting, Novel, Ethical, Relevant) and pilot studies to refine protocols .

Q. How to integrate this compound research data into broader neuropharmacology databases?

Use standardized formats (e.g., ISA-Tab for metadata) and ontologies (e.g., ChEBI for chemical entities). Deposit raw electrophysiology data in platforms like NeuroMorpho.org and link to publications via DOI. Adhere to FAIR data principles, ensuring machine-readable metadata and open licensing (CC BY 4.0) .