(S)-Propranolol-d7 Hydrochloride
Vue d'ensemble
Description
(S)-Propranolol-d7 Hydrochloride is a deuterated form of (S)-Propranolol, a beta-adrenergic receptor antagonist. The deuterium atoms replace the hydrogen atoms in the propranolol molecule, which can be useful in pharmacokinetic studies due to the isotope effect. This compound is primarily used in scientific research to study the pharmacokinetics and metabolism of propranolol.
Méthodes De Préparation
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.
Analyse Des Réactions Chimiques
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.
Applications De Recherche Scientifique
(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.
Mécanisme D'action
(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.
Comparaison Avec Des Composés Similaires
Similar Compounds
(S)-Propranolol: The non-deuterated form of the compound.
®-Propranolol: The enantiomer of (S)-Propranolol with different pharmacological properties.
Atenolol: Another beta-blocker with a different chemical structure but similar therapeutic effects.
Metoprolol: A beta-blocker with selective beta-1 adrenergic receptor antagonism.
Uniqueness
(S)-Propranolol-d7 Hydrochloride is unique due to the presence of deuterium atoms, which provide advantages in pharmacokinetic studies by reducing the rate of metabolic degradation. This makes it a valuable tool in drug development and research, offering insights into the behavior of propranolol and its analogs in biological systems.
Activité Biologique
(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
| Property | Value/Description |
|---|---|
| Receptor Affinity | β1AR Ki: 1.8 nM; β2AR Ki: 0.8 nM |
| IC50 (βAR) | 12 nM |
| Peak Plasma Concentration | 1-2 hours post-administration |
| Mean Clearance Rate | ~23 L/h |
| Half-life | 3.5 (1.5-25.6) hours |
| Primary Metabolism | CYP2D6, CYP1A2 |
Propriétés
Numéro CAS |
1346617-12-6 |
|---|---|
Formule moléculaire |
C16H22ClNO2 |
Poids moléculaire |
302.85 |
Nom IUPAC |
(2S)-1-(1,1,1,2,3,3,3-heptadeuteriopropan-2-ylamino)-3-naphthalen-1-yloxypropan-2-ol;hydrochloride |
InChI |
InChI=1S/C16H21NO2.ClH/c1-12(2)17-10-14(18)11-19-16-9-5-7-13-6-3-4-8-15(13)16;/h3-9,12,14,17-18H,10-11H2,1-2H3;1H/t14-;/m0./s1/i1D3,2D3,12D; |
Clé InChI |
ZMRUPTIKESYGQW-HLRQKBRWSA-N |
SMILES |
CC(C)NCC(COC1=CC=CC2=CC=CC=C21)O.Cl |
Synonymes |
(2S)-1-[(1-Methylethyl-d7)amino]-3-(1-naphthalenyloxy)-2-propanol Hydrochloride; _x000B_S-(-)-1-(Isopropyl-d7)amino-3-(1-naphthoxy)-2-propanol Hydrochloride; (-)-Propranolol-d7 Hydrochloride; (S)-(-)-Propranolol-d7 Hydrochloride; L-(-)-Propranolol-d7 Hydro |
Origine du produit |
United States |
Synthesis routes and methods
Procedure details
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