Dexpropranolol

Dexpropranolol can be synthesized through several synthetic routes. One common method involves the resolution of racemic propranolol using chiral agents to separate the dextrorotatory enantiomer. The reaction conditions typically involve the use of solvents like dimethyl sulfoxide (DMSO) and specific chiral catalysts . Industrial production methods may involve large-scale resolution processes and purification techniques to ensure the high enantiomeric purity of this compound.

Dexpropranolol undergoes various chemical reactions, including:

Oxidation: It can be oxidized using reagents like potassium permanganate or chromium trioxide to form corresponding naphthoquinones.

Reduction: Reduction reactions can be carried out using hydrogen gas in the presence of palladium on carbon to yield reduced derivatives.

Substitution: Nucleophilic substitution reactions can occur at the naphthalene ring, often using reagents like sodium hydride and alkyl halides.

The major products formed from these reactions depend on the specific reagents and conditions used.

Pharmacological Profile

Dexpropranolol exhibits local anesthetic properties similar to those of propranolol but with negligible beta-adrenergic receptor blocking activity. This distinct profile allows for potential applications in areas where traditional beta-blockers may not be suitable.

Key Characteristics of this compound

Clinical Applications

• Cardiovascular Conditions
  • This compound has been studied in the context of angina pectoris and exercise tolerance. A comparative study indicated that while this compound did not significantly affect exercise time, propranolol and practolol improved exercise tolerance in patients with angina . This suggests that this compound may not be as effective as its racemic counterpart in managing certain cardiovascular symptoms.
• Migraine Prophylaxis
  • Although propranolol is commonly used for migraine prevention, research into this compound's efficacy in this area is limited. However, understanding its mechanism may provide insights into alternative treatments for patients who cannot tolerate traditional beta-blockers .
• Psychological Effects
  • Emerging studies suggest that propranolol can influence emotional responses and implicit biases, raising questions about whether this compound could have similar effects without the associated beta-blocking properties. Research indicates that propranolol reduces implicit racial bias, potentially due to its effects on the autonomic nervous system . Further exploration into this compound's impact on psychological conditions could yield valuable insights.
• Post-Traumatic Stress Disorder (PTSD)
  • Propranolol has shown promise in reducing stress-related symptoms when administered after trauma. Investigating whether this compound could provide similar benefits without the side effects associated with beta blockade could be an important area of research .

Case Study 1: Exercise Tolerance in Angina Patients

A study comparing this compound with racemic propranolol and practolol revealed that while both propranolol and practolol improved exercise tolerance, this compound did not show significant effects. This highlights the importance of understanding the specific actions of each isomer in clinical settings .

Case Study 2: Psychological Impact

In a study examining the effects of propranolol on implicit racial bias, participants receiving propranolol scored lower on measures of subconscious bias compared to those receiving a placebo. This raises questions about whether this compound could modulate such biases without the cardiovascular implications of traditional beta-blockers .

Dexpropranolol exerts its effects by blocking beta-adrenergic receptors, which are involved in the response to catecholamines like adrenaline and noradrenaline. This blockade leads to a decrease in heart rate, blood pressure, and myocardial oxygen demand. The molecular targets include beta-1 and beta-2 adrenergic receptors, and the pathways involved are related to the inhibition of cyclic AMP production and subsequent downstream signaling .

Propranolol (Racemic Mixture)

• Structural Similarity: Dexpropranolol shares identical molecular structure (C16H21NO2) with propranolol but differs in stereochemistry at the chiral center .
• Pharmacological Activity: β-Blocking Potency: Propranolol’s (S)-enantiomer is responsible for >99% of β-blockade, while this compound contributes minimally . Noradrenaline Uptake Inhibition: Both enantiomers inhibit noradrenaline uptake equally, but only propranolol potentiates nerve-evoked vasoconstriction due to β-blockade . Clinical Effects: Propranolol reduces blood pressure and heart rate, whereas this compound lacks antihypertensive effects despite similar noradrenaline-blocking activity .

Table 1: Key Pharmacological Differences

4-Hydroxypropranolol (Metabolite)

• Metabolic Relationship: 4-Hydroxypropranolol is an active metabolite of propranolol with intrinsic β-blocking activity .
• Comparison: Potency: 4-Hydroxypropranolol has ~40% of propranolol’s β-blocking potency but longer half-life due to hepatic recirculation . Hemodynamic Effects: In dogs, 4-hydroxypropranolol reduces cardiac output less markedly than propranolol, making it a weaker negative inotrope .

Practolol (Cardioselective β1 Blocker)

• Selectivity: Practolol is β1-selective, unlike this compound’s non-selectivity .
• Clinical Utility: Practolol was historically used for angina but withdrawn due to side effects (e.g., oculomucocutaneous syndrome). This compound, while safer, lacks therapeutic β-blocking utility .

Atenolol (β1-Selective Blocker)

• Mechanism: Atenolol selectively blocks β1 receptors, reducing sympathetic nerve activity without affecting β2-mediated bronchodilation .

Research Findings and Clinical Implications

• Arrhythmia Models: Both this compound and propranolol prevent adrenaline-induced arrhythmias in cats, but the (S)-enantiomer requires 7.5-fold lower doses .
• Vascular Responses: this compound (50 mg/kg) fails to potentiate vascular responses to sympathetic nerve stimulation, unlike racemic propranolol, confirming its minimal β-blocking role .

Dexpropranolol is a selective beta-adrenergic antagonist derived from propranolol, primarily used in the management of various cardiovascular conditions. This article explores the biological activity of this compound, including its pharmacokinetics, mechanisms of action, therapeutic applications, and safety profile, supported by data tables and relevant case studies.

Pharmacokinetics

This compound exhibits distinct pharmacokinetic properties compared to its racemic counterpart, propranolol. Key pharmacokinetic parameters include:

This compound is cleared more rapidly than propranolol, primarily because it does not significantly affect hepatic blood flow, leading to a more predictable pharmacokinetic profile .

This compound functions by selectively blocking beta-adrenergic receptors, particularly β1 receptors in the heart. This blockade results in:

• Reduced heart rate : By inhibiting the effects of catecholamines on the heart.
• Decreased myocardial contractility : Leading to lower oxygen demand during stress.
• Vasodilation : Although less pronounced than with other beta-blockers.

These actions contribute to its therapeutic efficacy in managing hypertension and preventing angina pectoris .

Therapeutic Applications

This compound has been studied for various clinical applications:

• Hypertension : Clinical trials have demonstrated its effectiveness in lowering blood pressure compared to placebo and other antihypertensives.
• Anxiety Disorders : It is used off-label for performance anxiety due to its ability to mitigate physical symptoms like tachycardia and tremors.
• Migraine Prophylaxis : Some studies suggest it may help reduce the frequency of migraine attacks.

A meta-analysis indicated that this compound significantly reduces the risk of disease progression in infants with retinopathy of prematurity (ROP), showing a relative risk (RR) of 0.65 for stage progression compared to controls .

Safety Profile

While generally well-tolerated, this compound can cause adverse effects similar to other beta-blockers:

The increased risk of adverse events was noted in a meta-analysis involving infants treated with propranolol, indicating a need for careful monitoring during treatment .

Case Studies

Several case studies highlight the clinical efficacy of this compound:

• Case Study 1 : A 30-year-old male with generalized anxiety disorder reported significant improvement in symptoms after initiating treatment with this compound, particularly during public speaking engagements.
• Case Study 2 : An infant diagnosed with ROP showed marked improvement in disease stage after receiving this compound, reducing the need for laser therapy.

Basic Research Questions

Q. What are the key pharmacological properties of Dexpropranolol that distinguish it from its enantiomer, (S)-propranolol, in β-adrenergic receptor antagonism?

• Methodological Answer : Comparative studies should assess binding affinities (Ki values) for β1AR and β2AR using radioligand displacement assays. For example, this compound exhibits Ki values of 1.8 nM (β1AR) and 0.8 nM (β2AR), whereas (S)-propranolol shows higher potency . Dose-response curves in isolated tissue models (e.g., guinea pig atria for β1AR, trachea for β2AR) can further validate enantiomer-specific efficacy. Data should be analyzed using nonlinear regression to calculate EC50 values and statistical significance (e.g., t-tests for inter-group differences) .

Q. How should researchers design in vivo experiments to evaluate this compound’s cardiovascular effects while minimizing confounding variables?

• Methodological Answer : Use controlled animal models (e.g., rodents or cats) with standardized anesthesia protocols to isolate adrenergic responses. For instance, measure heart rate variability and arrhythmia incidence post-ouabain or cocaine administration, as this compound reverses ventricular tachycardia in these models . Randomize treatment groups, include vehicle controls, and blind outcome assessments to reduce bias. Data should be normalized to baseline measurements and analyzed via ANOVA with post-hoc corrections .

Q. What are the best practices for validating this compound’s enantiomeric purity in experimental samples?

• Methodological Answer : Employ chiral chromatography (e.g., HPLC with a chiral stationary phase) coupled with mass spectrometry to quantify enantiomeric excess. Calibrate methods using reference standards and report resolution factors (Rs > 1.5). Cross-validate with circular dichroism spectroscopy to confirm optical activity .

Advanced Research Questions

Q. How can contradictory findings regarding this compound’s enantiomer-specific activity in different species be systematically analyzed?

• Methodological Answer : Conduct a meta-analysis of existing data (e.g., cat vs. dog studies ) to identify species-dependent receptor expression or metabolic differences. Use sensitivity analysis to weigh confounding factors like dosage (e.g., (−)-propranolol requires lower doses for efficacy). Apply mixed-effects models to account for interspecies variability and publish negative results to mitigate publication bias .

Q. What experimental frameworks are optimal for investigating this compound’s off-target effects on non-adrenergic pathways?

• Methodological Answer : Utilize high-throughput screening (e.g., kinase panels or GPCR profiling) to identify off-target interactions. Combine with transcriptomic analysis (RNA-seq) of treated cell lines to detect downstream signaling perturbations. Validate hits using CRISPR knockouts or pharmacological inhibitors and report effect sizes with 95% confidence intervals .

Q. How should researchers address discrepancies between in vitro binding data and in vivo functional outcomes for this compound?

• Methodological Answer : Reconcile discrepancies by evaluating tissue-specific receptor density (e.g., β2AR dominance in bronchial tissue) and pharmacokinetic factors (e.g., plasma protein binding). Use physiologically based pharmacokinetic (PBPK) modeling to simulate tissue exposure levels and correlate with functional assays. Report limitations in translational relevance explicitly in discussions .

Q. Data Analysis & Interpretation

Q. What statistical approaches are recommended for analyzing dose-dependent responses in this compound studies with small sample sizes?

• Methodological Answer : Use non-parametric tests (e.g., Mann-Whitney U) for non-normal distributions and apply bootstrapping to estimate confidence intervals. For dose-response curves, Bayesian hierarchical models can improve precision in small datasets. Report effect sizes (e.g., Cohen’s d) and power calculations to contextualize findings .

Q. How can researchers ensure reproducibility when comparing this compound’s effects across heterogeneous experimental systems?

• Methodological Answer : Adopt FAIR data principles (Findable, Accessible, Interoperable, Reusable). Standardize protocols using guidelines like ARRIVE 2.0 for animal studies. Share raw data (e.g., electrophysiology traces, chromatograms) in public repositories and document metadata (e.g., batch numbers, instrument calibration) .

Q. Contradiction & Limitations

Q. What strategies are effective for resolving contradictions between historical and contemporary findings on this compound’s clinical potential?

• Methodological Answer : Perform systematic reviews to identify temporal trends (e.g., evolving diagnostic criteria or improved analytical techniques). Use GRADE criteria to assess evidence quality and highlight studies with robust blinding or randomization. Discuss how historical limitations (e.g., lack of enantiomer-specific assays) may skew interpretations .

Q. How should researchers frame the limitations of this compound studies in grant proposals or publications?

• Methodological Answer : Explicitly address limitations (e.g., translational gaps between animal models and humans) in the discussion section. Propose follow-up experiments (e.g., human induced pluripotent stem cell-derived cardiomyocytes) to mitigate these gaps. Use structured frameworks like PICOS (Population, Intervention, Comparison, Outcomes, Study Design) to align limitations with research objectives .

Q. Tables of Key Data