(R)-(-)-シタロプラム

Pharmacological Profile

(R)-(-)-citalopram is primarily recognized as a selective serotonin reuptake inhibitor (SSRI), but it exhibits distinct characteristics compared to its counterpart, (S)-(+)-citalopram. Research indicates that (R)-(-)-citalopram functions as an antagonist to (S)-(+)-citalopram, particularly in its effects on the serotonin transporter (SERT). In vitro studies have demonstrated that (R)-(-)-citalopram can inhibit the behavioral potentiation induced by (S)-(+)-citalopram, suggesting a complex interaction between the two enantiomers that may influence clinical outcomes in depression treatment .

Depression Treatment

Citalopram, including its enantiomers, is listed in the WHO model list of essential medicines for treating depressive disorders. Clinical studies have shown that nearly 80% of patients treated with citalopram for chronic or recurrent major depression experience significant improvement. The mean exit dose reported in these studies was approximately 41.8 mg/day, with remission rates around 28% to 33% depending on the assessment tool used .

Table 1: Summary of Citalopram Efficacy in Depression Treatment

Post-Traumatic Stress Disorder (PTSD)

Recent case studies have indicated that citalopram may also alleviate symptoms associated with PTSD. In two clinical cases, patients exhibited significant remission of PTSD symptoms following treatment with citalopram, underscoring its potential utility beyond traditional depression treatment .

Future Directions and Research Needs

While existing studies highlight the potential applications of (R)-(-)-citalopram, further research is warranted to fully elucidate its pharmacological profile and therapeutic benefits. Controlled trials are necessary to compare the efficacy of (R)-(-)-citalopram against other SSRIs and to explore its role in treating other psychiatric disorders.

Target of Action

®-(-)-Citalopram, also known as ®-citalopram, primarily targets the serotonin transporter (SERT), which plays a crucial role in the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron . By inhibiting SERT, ®-citalopram increases the availability of serotonin, a neurotransmitter that contributes to feelings of well-being and happiness .

Mode of Action

®-(-)-Citalopram binds to the serotonin transporter, blocking the reuptake of serotonin . This action leads to an increase in the concentration of serotonin in the synaptic cleft, enhancing serotoninergic neurotransmission .

Biochemical Pathways

The primary biochemical pathway affected by ®-(-)-citalopram is the serotoninergic pathway . By inhibiting the reuptake of serotonin, ®-(-)-citalopram indirectly influences various downstream effects related to mood regulation, sleep, appetite, and other physiological processes .

Pharmacokinetics

The pharmacokinetics of ®-(-)-citalopram involve its absorption, distribution, metabolism, and excretion (ADME). After oral administration, ®-(-)-citalopram is well absorbed and widely distributed throughout the body . It is metabolized primarily in the liver by the cytochrome P450 system, and the metabolites are excreted in urine . The compound’s bioavailability is affected by factors such as the individual’s metabolic rate, age, and overall health status .

Result of Action

At the molecular level, ®-(-)-citalopram’s action results in increased serotonin levels in the synaptic cleft . At the cellular level, this leads to enhanced serotoninergic neurotransmission, which can influence various physiological processes . Clinically, ®-(-)-citalopram is used for its antidepressant effects, which are thought to result from the enhanced serotoninergic neurotransmission .

Action Environment

The action, efficacy, and stability of ®-(-)-citalopram can be influenced by various environmental factors. For example, the presence of certain foods or other drugs can affect the absorption and metabolism of ®-(-)-citalopram . Additionally, factors such as pH levels and temperature can impact the stability of the compound . Understanding these factors is crucial for optimizing the therapeutic use of ®-(-)-citalopram .

Synthetic Routes and Reaction Conditions: The synthesis of ®-citalopram typically involves the resolution of racemic citalopram or the asymmetric synthesis starting from chiral precursors. One common method includes the use of chiral catalysts or chiral auxiliaries to achieve the desired enantiomeric purity. The reaction conditions often involve controlled temperatures and specific solvents to optimize the yield and purity of ®-citalopram.

Industrial Production Methods: Industrial production of ®-citalopram may involve large-scale resolution techniques such as chiral chromatography or crystallization. These methods are designed to separate the ®-enantiomer from the racemic mixture efficiently. The production process is optimized to ensure high purity and yield, meeting the stringent requirements for pharmaceutical applications.

Types of Reactions: ®-Citalopram undergoes various chemical reactions, including:

Oxidation: This reaction can be facilitated by oxidizing agents such as hydrogen peroxide or potassium permanganate.

Reduction: Reduction reactions may involve reagents like lithium aluminum hydride or sodium borohydride.

Substitution: Nucleophilic substitution reactions can occur, where functional groups in ®-citalopram are replaced by other nucleophiles.

Common Reagents and Conditions:

Oxidation: Hydrogen peroxide, potassium permanganate.

Reduction: Lithium aluminum hydride, sodium borohydride.

Substitution: Various nucleophiles depending on the desired substitution product.

Major Products Formed: The major products formed from these reactions depend on the specific reagents and conditions used. For example, oxidation may yield oxidized derivatives, while reduction can produce reduced forms of ®-citalopram.

(S)-Citalopram: The more active enantiomer of citalopram with higher affinity for the serotonin transporter.

Escitalopram: The pure (S)-enantiomer of citalopram, marketed as a separate antidepressant with improved efficacy and fewer side effects.

Fluoxetine: Another SSRI with a similar mechanism of action but different chemical structure.

Sertraline: An SSRI with a different chemical structure but similar therapeutic effects.

Uniqueness: ®-Citalopram is unique in its lower pharmacological activity compared to (S)-citalopram. This distinction is important in the context of drug development and therapeutic applications, as the (S)-enantiomer is often preferred for its higher efficacy and better safety profile.

(R)-(-)-citalopram, one of the enantiomers of the selective serotonin reuptake inhibitor (SSRI) citalopram, exhibits distinct biological activities that differentiate it from its counterpart, (S)-(+)-citalopram (escitalopram). Understanding the biological activity of (R)-(-)-citalopram is essential for evaluating its pharmacological implications, particularly in treating depression and anxiety disorders.

Overview of Citalopram and Its Enantiomers

Citalopram is a racemic mixture composed of two enantiomers: (R)-(-)-citalopram and (S)-(+)-citalopram. The latter is primarily responsible for the drug's antidepressant effects due to its higher affinity for the serotonin transporter (SERT), which mediates serotonin reuptake in the synaptic cleft. In contrast, (R)-(-)-citalopram has significantly lower affinity for SERT, approximately 30 to 40 times less than that of (S)-(+)-citalopram .

Interaction with Serotonin Transporter

(R)-(-)-citalopram acts as a competitive inhibitor of (S)-(+)-citalopram binding to SERT. This antagonistic behavior has been demonstrated in both in vitro and in vivo studies. For instance, (R)-(-)-citalopram was shown to inhibit the effects of (S)-(+)-citalopram on serotonin reuptake, leading to a reduction in the overall efficacy of citalopram .

Table 1: Comparative Affinities of Citalopram Enantiomers for SERT

Efficacy and Adverse Effects

Clinical studies have shown that while (S)-(+)-citalopram is effective in treating major depressive disorder, the presence of (R)-(-)-citalopram can lead to adverse effects and reduced therapeutic benefits. For example, a study involving patients with Alzheimer's disease indicated that the use of racemic citalopram resulted in diminished cognitive function, attributed largely to the effects of (R)-(-)-citalopram .

Case Study: CitAD Study Findings

• Participants: Patients with Alzheimer's disease
• Outcome: Decreased cognitive function as measured by the Mini-Mental State Examination (MMSE) scores
• Conclusion: The presence of (R)-(-)-citalopram correlated with poorer treatment outcomes compared to those receiving only the S-enantiomer .

Pharmacokinetics and Dynamics

The pharmacokinetic profile of (R)-(-)-citalopram shows rapid onset and offset kinetics when interacting with SERT. In contrast to the prolonged action seen with (S)-(+)-citalopram, which induces a long-lasting inhibition state, the effects of (R)-(-)-citalopram are more transient . This dynamic interaction is crucial for understanding how these enantiomers influence each other's pharmacological effects.

Summary of Findings

• Antagonistic Interaction: (R)-(-)-citalopram antagonizes the serotonergic effects of (S)-(+)-citalopram both in vitro and in vivo.
• Reduced Efficacy: The presence of (R) leads to decreased efficacy in treating depression and may contribute to adverse cognitive effects.
• Pharmacokinetic Differences: Rapid binding kinetics for (R) contrast with slower binding kinetics for (S), influencing therapeutic outcomes.