(S)-Propranolol-d7 Hydrochloride

Synthetic Routes and Reaction Conditions

The synthesis of (S)-Propranolol-d7 Hydrochloride involves the incorporation of deuterium atoms into the propranolol molecule. One common method is the catalytic exchange of hydrogen atoms with deuterium in the presence of a deuterium source such as deuterium oxide (D2O) or deuterated solvents. The reaction typically requires a catalyst like palladium on carbon (Pd/C) and is carried out under mild conditions to ensure selective deuteration.

Industrial Production Methods

Industrial production of this compound follows similar principles but on a larger scale. The process involves the use of high-pressure reactors and continuous flow systems to achieve efficient deuteration. The final product is purified using chromatographic techniques to ensure high purity and isotopic enrichment.

Types of Reactions

(S)-Propranolol-d7 Hydrochloride undergoes various chemical reactions, including:

Oxidation: The compound can be oxidized to form corresponding quinones or other oxidized derivatives.

Reduction: Reduction reactions can convert the compound back to its parent form or other reduced derivatives.

Substitution: The aromatic ring and hydroxyl groups can undergo substitution reactions with various electrophiles or nucleophiles.

Common Reagents and Conditions

Oxidation: Common oxidizing agents include potassium permanganate (KMnO4) and chromium trioxide (CrO3).

Reduction: Reducing agents such as sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4) are used.

Substitution: Reagents like halogens (Cl2, Br2) or nucleophiles (NH3, OH-) are employed under appropriate conditions.

Major Products Formed

The major products formed from these reactions depend on the specific conditions and reagents used. For example, oxidation can yield quinones, while reduction can produce alcohols or amines. Substitution reactions can introduce various functional groups onto the aromatic ring or hydroxyl groups.

(S)-Propranolol-d7 Hydrochloride has a wide range of applications in scientific research:

Pharmacokinetics: Used to study the absorption, distribution, metabolism, and excretion of propranolol in the body.

Metabolism Studies: Helps in identifying metabolic pathways and intermediates of propranolol.

Drug Development: Assists in the development of new beta-blockers and related compounds.

Isotope Effect Studies: Used to study the kinetic isotope effect and its impact on drug metabolism and pharmacokinetics.

(S)-Propranolol-d7 Hydrochloride exerts its effects by blocking beta-adrenergic receptors, which are involved in the regulation of heart rate, blood pressure, and other physiological functions. The deuterium atoms do not significantly alter the mechanism of action but can affect the metabolic stability and pharmacokinetics of the compound. The primary molecular targets are the beta-1 and beta-2 adrenergic receptors, and the pathways involved include the inhibition of cyclic AMP (cAMP) production and subsequent downstream signaling.

Key Properties :

• Purity : >98%
• Clinical Status: No clinical development reported; used exclusively in research .
• Applications : Analytical quantification, metabolic stability studies, and receptor binding assays .

Structural and Functional Analogues

Table 1: Comparative Analysis of β-Adrenergic Receptor Antagonists

Key Differentiators

Receptor Selectivity: (S)-Propranolol-d7 HCl and its non-deuterated parent, Propranolol HCl, are non-selective βAR antagonists, whereas (Rac)-Nebivolol-d4 is β1-selective . 4-Hydroxypropranolol-d7 HCl, an active metabolite of Propranolol, retains β-blocking activity but exhibits additional antioxidant properties .

Enantiomeric Specificity: The (S)-enantiomer in (S)-Propranolol-d7 HCl ensures targeted βAR binding, unlike racemic mixtures like (Rac)-Nebivolol-d4 or Propranolol HCl .

Deuterium Labeling: Deuterated compounds (e.g., (S)-Propranolol-d7 HCl, (S)-Carvedilol-d4) are metabolically stable, making them ideal for tracer studies. In contrast, non-deuterated analogs like (S)-Carvedilol are used therapeutically .

Clinical vs. Research Use: While Propranolol HCl and (S)-Carvedilol are clinically approved, deuterated variants are restricted to research due to a lack of clinical data .

Pharmacokinetic and Metabolic Considerations

• Absorption: Propranolol HCl is well-absorbed orally, but deuterated forms like (S)-Propranolol-d7 HCl may exhibit altered pharmacokinetics due to the kinetic isotope effect, though specific data are unavailable .
• Metabolism: 4-Hydroxypropranolol-d7 HCl, a major metabolite, shares β-blocking activity but has distinct redox properties, highlighting differences in downstream effects compared to the parent drug .

(S)-Propranolol-d7 hydrochloride is a deuterium-labeled derivative of propranolol, a well-known non-selective beta-adrenergic receptor antagonist used primarily for cardiovascular conditions. This article delves into the biological activity of this compound, focusing on its pharmacological properties, metabolic pathways, and clinical implications based on diverse sources.

Overview of Propranolol

Propranolol acts by blocking beta-adrenergic receptors, specifically the β1 and β2 subtypes. It is commonly used to treat hypertension, angina pectoris, cardiac arrhythmias, and anxiety disorders. Its high affinity for β1 and β2 receptors is evidenced by Ki values of 1.8 nM and 0.8 nM, respectively . The deuterium labeling in (S)-Propranolol-d7 allows for enhanced tracking in pharmacokinetic studies without altering the compound's biological activity.

Pharmacodynamics

Mechanism of Action

This compound functions as a competitive antagonist at beta-adrenergic receptors. This antagonism leads to decreased heart rate and myocardial contractility, which are beneficial in managing conditions like hypertension and anxiety.

Binding Affinity

The binding affinity of (S)-Propranolol-d7 to beta-adrenergic receptors is similar to that of its non-labeled counterpart. The inhibition constant (IC50) for [3H]-DHA binding in rat brain membranes is approximately 12 nM . This indicates that the deuterated compound retains effective interaction with target receptors.

Metabolism and Pharmacokinetics

Metabolic Pathways

(S)-Propranolol-d7 undergoes similar metabolic processes as propranolol. It is primarily metabolized in the liver via cytochrome P450 enzymes, particularly CYP2D6 and CYP1A2. The deuterium labeling aids in distinguishing the compound from its metabolites during pharmacokinetic studies.

Pharmacokinetic Profile

Clinical studies demonstrate that propranolol reaches peak plasma concentrations within 1 to 2 hours post-administration, with a mean clearance rate of approximately 23 L/h . The terminal elimination half-life ranges from 3.5 hours to 25.6 hours, depending on individual metabolic rates .

Clinical Efficacy

Case Studies

• Infantile Hemangioma Treatment : A notable application of propranolol is in treating infantile hemangiomas. A Phase 2/3 study showed significant resolution of lesions in infants treated with propranolol compared to placebo groups . The efficacy was dose-dependent, with higher doses correlating with better outcomes.
• Anxiety Disorders : Propranolol has also been studied for its effects on performance anxiety. Clinical trials indicate that it effectively reduces physiological symptoms associated with anxiety without sedative effects, making it a preferred choice for patients needing acute management .

Safety Profile

Toxicology Studies

Toxicological assessments indicate that propranolol does not present significant genotoxic risks. Studies involving juvenile rats showed no adverse effects on long bone growth or cognitive functions at therapeutic doses . However, some studies reported DNA fragmentation at high doses in vitro, although no significant hepatic DNA damage was observed in vivo .

Summary Table of Biological Activity

Basic Research Questions

Q. How is (S)-Propranolol-d7 Hydrochloride used as an internal standard in quantitative analysis?

• Methodological Answer : this compound is employed as a deuterated internal standard (IS) in liquid chromatography-mass spectrometry (LC-MS) or gas chromatography (GC) workflows to quantify propranolol and its metabolites. The deuterium labeling minimizes isotopic interference, ensuring precise calibration. For example, a 100 μg/mL solution in methanol with 5% 1 M HCl (as per certified reference material standards) is used to spike samples, enabling accurate normalization of extraction efficiency and ionization variability .
• Key Data :

Q. What is the role of this compound in studying β-adrenergic receptor (βAR) interactions?

• Methodological Answer : As a nonselective βAR antagonist, this compound is used to investigate receptor binding kinetics and competitive inhibition. Researchers employ radioligand displacement assays (e.g., using ³H-CGP 12177) to measure its affinity (Ki) for β1AR (1.8 nM) and β2AR (0.8 nM). The deuterated form allows differentiation from endogenous propranolol in tissue samples, improving specificity in pharmacokinetic studies .

Q. How does the deuterium labeling affect the physicochemical properties of this compound?

• Methodological Answer : Deuterium substitution at seven positions increases molecular mass by ~7 Da, which is critical for distinguishing it from non-deuterated propranolol in MS-based assays. However, its solubility (100 mg/mL in DMSO) and logP (~2.97) remain comparable to the non-deuterated form, ensuring similar bioavailability in in vitro models .

Advanced Research Questions

Q. How can researchers resolve discrepancies in reported βAR binding affinities for this compound?

• Methodological Answer : Variations in pA2 values (e.g., 8.24 for β1AR vs. 8.26 for β2AR in metabolite studies) may arise from differences in assay conditions (e.g., cell type, temperature, or buffer pH). To address this:

Standardize experimental protocols (e.g., NIH guidelines for preclinical studies ).

Use orthogonal methods (e.g., surface plasmon resonance vs. functional cAMP assays).

Validate findings with structural analogs like 4-Hydroxypropranolol-d7, which shares similar receptor interactions .

Q. What experimental designs optimize deuterium incorporation efficiency during (S)-Propranolol-d7 synthesis?

• Methodological Answer : Deuterium labeling efficiency depends on reaction solvents (e.g., deuterated methanol), catalysts (e.g., Pd/C in D₂O), and purification steps. Advanced protocols include:

• Isotopic Purity Validation : Use NMR (²H integration) and high-resolution MS to confirm ≥98% deuteration .
• Stability Testing : Assess isotopic exchange under storage conditions (e.g., pH, temperature) to prevent back-exchange .

Q. How can researchers model the environmental fate of this compound in aquatic systems?

• Methodological Answer : Environmental risk assessments require:

Adsorption Studies : Measure organic carbon-normalized adsorption coefficients (Koc) using batch equilibrium experiments.

Degradation Analysis : Use LC-MS/MS to track deuterium retention in hydrolysis or photolysis products .

• Key Parameter : Propranolol hydrochloride has a Kd of 0.5–1.2 L/kg in sediment, suggesting moderate mobility in aquatic environments .

Q. What statistical approaches are recommended for optimizing (S)-Propranolol-d7 formulations in sustained-release systems?

• Methodological Answer : Box-Behnken experimental designs can model the impact of variables like coating thickness and plasticizer concentration on drug release kinetics (e.g., t85, time for 85% release). Desirability functions integrate multiple responses (e.g., dissolution profile vs. process duration) to identify optimal conditions .
• Example Data :

Q. Data Contradiction Analysis

Q. Why do studies report conflicting antioxidant activities for propranolol metabolites like 4-Hydroxypropranolol-d7?

• Resolution Strategy : Contradictions may stem from assay interference (e.g., redox-active buffers) or metabolite stability. Recommendations:

Use cell-free systems (e.g., DPPH radical scavenging assays) to isolate antioxidant effects.

Compare results across standardized models (e.g., H9c2 cardiomyocytes vs. HepG2 hepatocytes) .