Chlorpromazine

Derivation from Phenothiazine Chemistry and Antihistamine Research

This compound (CPZ) is a synthetic compound derived from the phenothiazine chemical structure physio-pedia.comwikipedia.org. Phenothiazines were initially investigated for their potential as antihistamines, with compounds like promethazine showing promise in this area scielo.br. Researchers at the French pharmaceutical company Rhône-Poulenc were actively exploring derivatives of phenothiazine for various medical applications scielo.br. This line of research led to the synthesis of this compound, which was found to possess potent antihistaminic and sedative effects scielo.br.

Initial Observations in Anesthesiology and "Artificial Hibernation"

The therapeutic potential of this compound beyond its antihistaminic properties began to emerge through observations in surgical settings. French surgeon Henri Laborit, in his work with surgical shock and anesthesia in the late 1940s and early 1950s, explored the use of promethazine and later this compound as part of a "lytic cocktail" scielo.br. Laborit hypothesized that this combination could induce a state of "artificial hibernation," a controlled hypothermia that would reduce metabolic activity and protect the body during surgery scielo.br.

Patients treated with this compound in this context exhibited a remarkable calmness and detachment, a state Laborit termed "desintéressement" scielo.br. This profound calming effect, even in the absence of deep anesthesia, suggested that this compound might have significant psychotropic properties. These observations in anesthesiology laid the groundwork for exploring its use in psychiatric disorders, particularly those characterized by agitation and severe behavioral disturbances scielo.br.

Pioneering Clinical Applications in Psychotic Disorders

Following Laborit's findings, French psychiatrists Jean Delay and Pierre Deniker, along with their colleagues, began systematically investigating this compound's effects on patients with severe mental illnesses, particularly those suffering from psychosis and schizophrenia scielo.br. Their early clinical trials, starting in 1952, demonstrated that this compound could significantly reduce psychotic symptoms such as hallucinations, delusions, agitation, and disorganized behavior scielo.br. Patients who had been severely incapacitated by their conditions often showed marked improvement, becoming more communicative, organized, and responsive to their environment scielo.br.

This compound's ability to calm agitated patients and reduce the severity of psychotic symptoms was unprecedented. It offered the first effective pharmacological tool to manage the core symptoms of schizophrenia and other psychotic disorders, moving away from purely custodial or physically intrusive treatments scielo.brphysio-pedia.comwikipedia.org. This marked a pivotal shift from containment to treatment, offering hope for recovery and improved quality of life for many individuals previously considered untreatable wikipedia.org.

International Dissemination and Acceptance in Psychiatry

The groundbreaking results from French clinical trials rapidly led to the international dissemination of this compound. It was introduced into clinical practice in the United States in 1954 under the brand name Thorazine wikipedia.org. The drug's efficacy in managing severe psychiatric symptoms, particularly psychosis, led to its widespread adoption by psychiatrists worldwide nih.govupenn.edunih.govwikipedia.org.

This compound's introduction is widely credited with initiating the psychopharmacological revolution, fundamentally changing how mental illnesses were understood and treated scielo.br. It facilitated the deinstitutionalization movement by making it possible for many patients to live outside of psychiatric hospitals, and it spurred extensive research into other psychoactive medications wikipedia.org. By the late 1950s and early 1960s, this compound had become a cornerstone of psychiatric treatment, a benchmark against which new antipsychotic medications would be measured cochranelibrary.com. Its impact was so profound that it is often referred to as the first "major tranquilizer" and a drug that redefined the possibilities of psychiatric care scielo.br.

Differential Affinity and Receptor Selectivity Profiles Compared to Other Antipsychotics

Antagonism at 5-HT2, 5-HT6, and 5-HT7 Serotonin Receptors

Effects on NMDA Receptor Mechanisms, Including Zn Site Interactions

This compound also significantly impacts N-methyl-D-aspartate (NMDA) receptor function. clinmedjournals.orgnih.gov It can act as an antagonist at NMDA receptors, in part by interacting with the zinc (Zn) binding site on the receptor complex. nih.govresearchgate.netresearchgate.net This interaction is complex, with this compound exhibiting both Zn++-like and Mg++-like effects at different concentrations. nih.gov At low concentrations, it slows the dissociation of [3H]MK801, a marker for the NMDA receptor channel, while at higher concentrations, it increases the dissociation rate. nih.gov This suggests a multifaceted interaction with the NMDA receptor complex. The inhibition of NMDA receptors by this compound occurs at clinically relevant low micromolar concentrations and displays a voltage- and magnesium-dependent open channel blocking mechanism. researchgate.netnih.gov

Implications for Excitatory Neurotransmission and Neurotrophic Effects

The modulation of both AMPA and NMDA receptors by this compound has significant implications for excitatory neurotransmission and neurotrophic processes. ijpp.comclinmedjournals.org By altering the activity of these critical glutamate receptors, this compound can influence synaptic plasticity, which is fundamental for learning and memory. clinmedjournals.org Some studies have described the effects of this compound on glutamatergic receptor mechanisms as having "neurotrophic effects," as it modifies the amplitude and temporal characteristics of receptor activity. clinmedjournals.orgijpp.comclinmedjournals.org

Influence on GABA-A Receptor Binding and Unbinding Kinetics

Studies utilizing patch-clamp techniques on cultured hippocampal neurons have revealed that this compound affects the binding and unbinding kinetics of GABA to GABA-A receptors. nih.govjneurosci.org Experimental data and model simulations suggest that this compound decreases the binding rate constant (k_on) and increases the unbinding rate constant (k_off) of GABA-A receptors. nih.govnih.govjneurosci.org

This alteration in kinetics has significant functional consequences. The reduction in the binding rate (k_on) by this compound makes the binding reaction a rate-limiting step. nih.govjneurosci.org Consequently, the brief presence of GABA in the synaptic cleft during a miniature inhibitory postsynaptic current (mIPSC) is insufficient to activate the receptors to the same degree as in control conditions. nih.govnih.govjneurosci.org This leads to a reduction in the amplitude of mIPSCs. nih.gov

Simultaneously, the increase in the unbinding rate (k_off) is the proposed mechanism for the accelerated decay phase of mIPSCs observed in the presence of this compound. nih.govnih.govjneurosci.org This faster unbinding of GABA from the receptor shortens the duration of the channel opening, leading to a quicker decay of the inhibitory current. nih.gov The effect of this compound on the rise time of GABA-evoked currents is dose-dependent, with higher concentrations causing a more significant slowing of the current onset. nih.govjneurosci.org

Table 1: Effect of this compound on the Rise Time of GABA-Evoked Currents

Data from experiments on cultured hippocampal neurons. The rise time of GABA-evoked currents was measured in the absence and presence of 100 μM this compound. The increase in rise time indicates a slower onset of the current. nih.gov

Effects on Miniature Inhibitory Postsynaptic Currents (mIPSCs)

This compound has been shown to significantly alter the characteristics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. nih.govjneurosci.org These currents represent the postsynaptic response to the spontaneous release of a single quantum of GABA from a presynaptic terminal.

Specifically, this compound reduces the amplitude and accelerates the decay of mIPSCs in a dose-dependent manner. nih.govjneurosci.org For instance, bath application of this compound at concentrations of 10, 30, and 100 μM resulted in a progressive decrease in mIPSC amplitude. jneurosci.org While 100 μM this compound reduced the mIPSC amplitude by approximately 90%, it only caused about a 30% depression of responses evoked by direct application of GABA, highlighting a more pronounced effect on synaptic currents. nih.govjneurosci.org

The acceleration of the mIPSC decay kinetics is also a prominent effect of this compound. nih.govjneurosci.org This is evident when comparing the normalized current traces in control conditions and in the presence of the drug, where the decay phase is clearly faster with this compound. nih.gov This effect, as mentioned earlier, is attributed to the increased unbinding rate of GABA from its receptors. nih.govjneurosci.org

Table 2: Dose-Dependent Effect of this compound on mIPSC Amplitude

Data showing the dose-dependent reduction in the amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in the presence of varying concentrations of this compound. jneurosci.org

Alterations in Membrane Permeability and Fluidity

This compound has been demonstrated to increase the permeability and fluidity of cellular membranes. nih.govnih.gov This effect is concentration-dependent. tandfonline.comnih.gov Studies using rat brain slices have shown that CPZ can induce the leakage of intracellular components, suggesting the formation of transient pores or a general destabilization of the membrane. nih.gov This increased permeability is thought to be a result of the drug intercalating into the lipid bilayer, which disrupts the ordered packing of phospholipids. oncotarget.comresearchgate.net

The interaction of this compound with the membrane also leads to an increase in membrane fluidity. nih.gov This has been observed through techniques such as fluorescence polarization. nih.govnih.gov An increase in fluidity implies a more disordered state of the lipid acyl chains within the membrane. nih.govoncotarget.com This fluidizing effect is influenced by the lipid composition of the membrane, particularly the cholesterol content. annualreviews.org For instance, in membranes with low cholesterol, this compound can cause an ordering effect at lower concentrations, which transitions to a disordering effect at higher concentrations or in high-cholesterol membranes. annualreviews.org

Interactions with Negatively Charged Membrane Phospholipids and Polarity Shifts

This compound, being a cationic amphiphile at physiological pH, exhibits a strong affinity for negatively charged phospholipids, such as phosphatidylserine, which are often enriched in the inner leaflet of the plasma membrane. portlandpress.comnih.govnih.gov This electrostatic attraction plays a crucial role in its membrane interactions. nih.govresearchgate.net

The binding of this compound to these anionic lipids can neutralize their negative charge. oncotarget.com This neutralization has significant consequences for membrane-associated proteins that rely on electrostatic interactions for their localization and function. oncotarget.com A notable example is the oncogenic protein K-Ras4B(G12V), which anchors to the membrane through interactions with negatively charged phospholipids. oncotarget.com this compound has been shown to dislodge K-Ras4B(G12V) from the membrane by neutralizing these charges, thereby inhibiting its signaling functions. oncotarget.com

This interaction also leads to a shift in the polarity of the membrane environment. rsc.org The insertion of the hydrophobic tricyclic ring of this compound into the lipid bilayer, coupled with the presence of its polar side chain at the interface, alters the local dielectric properties. tandfonline.comresearchgate.net This change in polarity can be observed by the enhanced fluorescence of this compound itself upon membrane insertion. rsc.org The drug's presence at the lipid interfacial region allows it to interact with both the headgroups and the acyl tails of the phospholipids, further contributing to the destabilization and altered polarity of the membrane. rsc.org

Effects on Calcium Ion (Ca²⁺) Signaling Pathways

This compound has complex and multifaceted effects on intracellular calcium (Ca²⁺) signaling. It has been shown to inhibit store-operated calcium entry (SOCE), a crucial mechanism for replenishing intracellular calcium stores and sustaining calcium signals. nih.gov In PC12 cells, this compound inhibited the sustained phase of Ca²⁺ increase induced by bradykinin, without affecting the initial release from internal stores. nih.gov This suggests a direct inhibitory effect on the channels responsible for SOCE. nih.gov

Conversely, in human glioblastoma cells (GBM 8401), this compound has been found to increase intracellular Ca²⁺ concentrations. nih.govresearchgate.net This increase is mediated by both Ca²⁺ influx through store-operated Ca²⁺ channels and phospholipase C (PLC)-dependent Ca²⁺ release from the endoplasmic reticulum. nih.govresearchgate.net The chelation of this excess intracellular Ca²⁺ was shown to reduce this compound-induced cytotoxicity in these cancer cells, indicating that the dysregulation of Ca²⁺ homeostasis is a key component of its anti-tumor activity. nih.gov

Mechanistic Target of Rapamycin Complex 1 (mTORC1) Signaling Regulation

The mTORC1 signaling pathway is a central regulator of cell growth, proliferation, and metabolism. This compound has been identified as an inhibitor of the mTORC1 pathway in various cancer cell lines, including glioma and oral cancer cells. oncotarget.comresearchgate.netnih.gov It achieves this inhibition by reducing the phosphorylation levels of key downstream effectors of mTORC1, such as Akt and p70S6K. oncotarget.comnih.gov In PTEN-null glioma cells, where the Akt/mTOR pathway is constitutively active, this compound treatment led to cell cycle arrest and autophagic cell death. oncotarget.comoup.com The inhibition of mTORC1 signaling is a significant contributor to the anti-proliferative and pro-autophagic effects of this compound. nih.govoup.com

Induction of Transcription Factor EB (TFEB) Nuclear Translocation

Recent studies have revealed that this compound can induce the nuclear translocation of Transcription Factor EB (TFEB). frontiersin.orgnih.govrcsi.com TFEB is a master regulator of lysosome biogenesis and autophagy. frontiersin.org Under normal conditions, mTORC1 phosphorylates TFEB, retaining it in the cytoplasm. nih.gov By inhibiting mTORC1 activity, this compound prevents this phosphorylation, leading to TFEB's translocation into the nucleus. frontiersin.orgnih.gov This effect appears to be mediated through the Rag GTPases, which are upstream regulators of mTORC1. frontiersin.orgnih.gov Once in the nucleus, TFEB can activate the transcription of genes involved in autophagy and lysosomal function. nih.gov However, it has also been noted that while promoting the machinery for autophagy, this compound can also block the fusion of autophagosomes with lysosomes, leading to an accumulation of immature autophagosomes. frontiersin.org

Blockade of Autophagosome-Lysosome Fusion

A primary mechanism underlying the accumulation of autophagosomes is the blockade of their fusion with lysosomes. researchgate.netnih.govmdpi.comoup.com This fusion is a critical step in the autophagic process, as the acidic environment and hydrolytic enzymes within the lysosome are necessary for the breakdown of the autophagosome's contents. By inhibiting this fusion, this compound effectively halts the final stage of autophagy, leading to a build-up of undegraded autophagic vesicles. researchgate.net This effect is similar to that of other agents known to disrupt lysosomal function, such as chloroquine. oup.combrieflands.com The inability of autophagosomes to merge with lysosomes results in a dysfunctional pathway where cellular waste is sequestered but not eliminated.

Role of Rag GTPases in Autophagic Impairment

Recent research has elucidated the role of Rag GTPases in the autophagic impairment caused by this compound. researchgate.netmdpi.comoup.com Rag GTPases are key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, which is a central controller of cell growth and autophagy. researchgate.net this compound treatment has been shown to induce the nuclear translocation of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, in a manner dependent on Rag GTPases. researchgate.netmdpi.comoup.com Specifically, CPZ appears to decrease the activity of Rag GTPases, leading to the dissociation of mTORC1 from the lysosome and subsequent nuclear entry of TFEB. researchgate.net While this would typically promote autophagy, the concurrent blockade of autophagosome-lysosome fusion creates a state of autophagic stress. Interestingly, the expression of an active form of Rag GTPase heterodimers has been found to alleviate the accumulation of autophagosomes induced by CPZ, underscoring the significant contribution of the Rag GTPase-mTORC1-TFEB signaling axis to this compound-induced autophagic dysfunction. researchgate.netmdpi.com

Inhibition of Cytochrome c Oxidase (CcO) Activity

This compound has been demonstrated to inhibit the activity of cytochrome c oxidase (CcO), also known as complex IV of the mitochondrial electron transport chain. nih.govnih.govoncotarget.com This inhibitory effect has been observed to be particularly selective in certain pathological contexts. For instance, in chemoresistant glioma cells, this compound selectively inhibits CcO activity, an effect not seen in their chemosensitive counterparts. nih.govnih.gov This selectivity is linked to the expression of different isoforms of a CcO subunit. Chemoresistant glioma cells often exhibit a switch from expressing the COX4-2 subunit isoform to the COX4-1 isoform. nih.govnih.gov Computer-simulated docking studies suggest that this compound binds more effectively to CcO containing the COX4-1 subunit. nih.govnih.gov The direct interaction and inhibition of CcO by this compound have been confirmed in studies using purified enzyme, with a reported IC50 value of 25.82 ± 3.75 μM for bovine heart CcO. nih.gov

Effects on Oxygen Consumption and Glucose Oxidation

This compound also influences glucose metabolism. Research indicates that it inhibits the oxidation of glucose. researchgate.netcapes.gov.br In guinea pig brain tissue, this compound was found to inhibit the oxidation of glucose via the tricarboxylic acid (TCA) cycle. capes.gov.br Furthermore, in canine thyroid slices, this compound blocked the TSH-induced stimulation of glucose-1-14C oxidation to 14CO2, suggesting an interference with metabolic pathways linked to specific cellular functions. oup.com While prolonged treatment with low doses of CPZ did not appear to alter glucose tolerance in human subjects, higher acute doses have been suggested to potentially inhibit insulin secretion and induce hyperglycemia. nih.gov

Inhibition of DNA Synthesis and [³H]Thymidine Incorporation

One of the earliest recognized anticancer mechanisms of this compound is its ability to inhibit DNA synthesis. nih.gov This effect has been consistently observed in both cellular and cell-free systems, suggesting a direct interference with the enzymatic machinery of DNA replication. nih.govnih.gov

A common method to measure DNA synthesis is the [³H]thymidine incorporation assay, which tracks the integration of a radiolabeled nucleoside into newly synthesized DNA during cell division. thermofisher.comresearchgate.net Studies using this technique have provided quantitative evidence of this compound's inhibitory effects. For instance, early research in 1965 demonstrated that this compound reduces the incorporation of [³H]thymidine into human bone marrow cells. nih.govresearchgate.net

Further research has elaborated on this inhibitory action in various models:

In developing rat brains, this compound administration led to a severe and dose-dependent reduction in the rate of [³H]thymidine incorporation into DNA. nih.gov The synthesis rate dropped to less than 40% of control levels in the forebrain and 60% in the cerebellum within hours of administration. nih.gov

In the protozoan Tetrahymena, a 20-minute preincubation with 14.7 µM of this compound inhibited DNA synthesis by 46%. nih.gov The compound was also found to inhibit the incorporation of labeled thymidine into the thymidine triphosphate pool in this organism. nih.gov

In Meth A sarcoma cells, this compound was shown to inhibit DNA synthesis both in cell cultures and in isolated nuclei. nih.gov

Studies on the fungus Candida albicans also revealed that this compound affects DNA synthesis, which is linked to its antifungal activity. oup.comoup.com

This body of evidence confirms that this compound's impact on cell proliferation is directly linked to its capacity to halt or slow down the synthesis of DNA. nih.govtandfonline.com

Table 1: Effect of this compound on DNA Synthesis and [³H]Thymidine Incorporation in Various Cell Types

Effects on Cell Cycle Parameters and Mitotic Activity

This compound exerts significant influence over the cell cycle, the ordered sequence of events that leads to cell division and duplication. Its interference can lead to cell cycle arrest at various checkpoints, thereby inhibiting proliferation. nih.govoncotarget.com

In several cancer cell lines, this compound has been shown to induce cell cycle arrest. For example:

In colorectal cancer (CRC) cells, this compound was found to effectively suppress proliferation by inducing G2/M phase cell cycle arrest. nih.gov This arrest was associated with the reduced activity of the cdc2/cyclin B1 complex, a key regulator of the G2/M transition. nih.gov Specifically, it suppressed the expression of cyclin B1, cdc2, and cdc25c. nih.gov

In rat C6 glioma cells, this compound treatment resulted in cell cycle arrest and an increase in the level of p21Waf1/Cip1, which is an inhibitor of the cyclin E/CDK2 complex. mdpi.com

In the fungus Candida albicans, this compound was observed to affect cell proliferation by arresting cells at the G1/S boundary, delaying the progression of cells from the G1 phase into the S phase. oup.comoup.com

Beyond arresting the cell cycle, this compound can also disrupt mitotic activity. Mitotic arrest has been observed in colorectal cell lines, where this compound inhibits the mitotic kinesin KSP/Eg5. oncotarget.comfrontiersin.org This inhibition leads to the formation of monopolar spindles, a cellular defect that prevents proper chromosome segregation and ultimately halts cell division, leading to an accumulation of cells in the G2/M phase. oncotarget.com In the developing rat brain, this compound significantly reduced mitotic activity in the cerebellar external granular layer. nih.gov

However, in some contexts, such as in developing rat brain subependymal cells, analysis of cell cycle parameters showed no significant changes, although the labelling index was reduced, suggesting an increased turnover time. nih.gov Similarly, in certain chemoresistant glioma cells, the antiproliferative effect was attributed to cell cycle arrest rather than an increase in apoptosis. scienceopen.com

Table 2: Effects of this compound on Cell Cycle and Mitotic Activity

Alterations in Manganese Concentration

Chronic administration of this compound has been shown to significantly increase manganese concentrations in specific brain regions of guinea pigs. Notably, manganese levels rose significantly in the caudate nucleus and the cerebellar hemisphere following prolonged this compound exposure capes.gov.br.

Changes in Iron Content

Research indicates that chronic this compound treatment can lead to an increase in iron concentration within the brain. Specifically, iron concentration rose most significantly in the caudate nucleus of guinea pigs after long-term administration of the drug capes.gov.br. Further experimental evidence suggests that this compound can stimulate iron uptake by synaptosomes in the rat brain, enhancing the uptake of iron from both iron-citrate and iron-transferrin donors, particularly in cortical synaptosomes nih.gov. Perturbations in iron homeostasis have been linked to neuroleptic-induced extrapyramidal motor side-effects, suggesting a potential role for this compound's influence on iron in these phenomena nih.govembopress.org.

Decreases in Copper Content

Studies have reported a decrease in copper content across all examined brain regions in guinea pigs following chronic this compound administration capes.gov.br. Copper is essential for various brain functions, including iron homeostasis, myelination, and neurotransmitter synthesis, making its reduction a significant observation nih.gov.

Table 1: Impact of Chronic this compound Administration on Trace Metal Concentrations in Guinea Pig Brain Regions