Norverapamil

Synthetic Routes and Reaction Conditions: The synthesis of norverapamil typically involves the demethylation of verapamil. One common method includes reacting verapamil with 1-chloroethyl chloroformate in an aprotic solvent. The reaction is carried out at temperatures ranging from 10°C to 80°C, resulting in the formation of a quaternary ammonium salt. This intermediate is then subjected to further reaction to remove the methyl group, yielding this compound .

Industrial Production Methods: Industrial production of this compound follows similar synthetic routes but on a larger scale. The process is optimized for high conversion rates and ease of separation. The use of cost-effective raw materials and controlled reaction conditions ensures efficient production .

Types of Reactions: Norverapamil undergoes various chemical reactions, including:

Reduction: Involves the removal of oxygen or the addition of hydrogen, typically using reducing agents.

Substitution: Involves the replacement of one functional group with another, often using nucleophiles or electrophiles.

Common Reagents and Conditions:

Oxidation: Common oxidizing agents include potassium permanganate and chromium trioxide.

Reduction: Common reducing agents include lithium aluminum hydride and sodium borohydride.

Substitution: Common reagents include halogens and alkylating agents.

Major Products: The major products formed from these reactions depend on the specific conditions and reagents used. For example, oxidation may yield hydroxylated derivatives, while reduction may produce deoxygenated compounds .

Pharmacological Properties

Norverapamil exhibits notable pharmacological properties that make it a candidate for addressing several medical challenges:

• Multidrug Resistance Reversal : this compound has been shown to be more effective than verapamil in reversing multidrug resistance (MDR) in cancer therapy. It operates by inhibiting P-glycoprotein, a key player in drug efflux mechanisms that contribute to MDR. Compared to verapamil, this compound has significantly reduced cardiotoxicity, making it a safer alternative for patients undergoing chemotherapy .
• Antitubercular Activity : Recent studies indicate that this compound can inhibit macrophage-induced tolerance to multiple anti-tubercular drugs. It has been demonstrated to reduce intracellular growth of Mycobacterium tuberculosis, suggesting its potential role in shortening tuberculosis treatment regimens .

Synthesis and Production

The synthesis of this compound remains a critical area of research due to its therapeutic potential:

• Biocatalytic Methods : Innovative approaches using cytochrome P450 enzymes have been developed for the efficient production of this compound. A study highlighted the use of CYP105D1 from Streptomyces griseus for selective N-demethylation of verapamil, resulting in high yields under mild conditions. This method is anticipated to enhance the production capabilities within the pharmaceutical industry .

Clinical Applications

This compound's clinical relevance is underscored by its pharmacokinetic properties and therapeutic efficacy:

• Pediatric Use : A study measuring plasma levels of verapamil and this compound in children revealed important insights into their pharmacokinetics. The findings indicated variability in drug concentrations based on age and dosage, highlighting the need for tailored dosing strategies in pediatric populations .
• Drug Interaction Studies : this compound has been included in pharmacokinetic models assessing drug-drug interactions (DDIs). Its interaction with various medications has been studied to predict potential adverse effects and optimize therapeutic regimens .

Data Table: Summary of this compound Applications

Case Study 1: Multidrug Resistance Reversal

In a controlled study, this compound was administered alongside standard chemotherapy agents to evaluate its efficacy in reversing MDR. Results demonstrated a significant reduction in tumor cell viability compared to controls treated with chemotherapy alone.

Case Study 2: Tuberculosis Treatment

A clinical trial involving patients with drug-resistant tuberculosis assessed the impact of adding this compound to standard treatment regimens. The trial reported improved outcomes with reduced treatment duration and enhanced tolerability.

Norverapamil exerts its effects by inhibiting the influx of calcium ions through L-type calcium channels in the cell membrane. This inhibition leads to the relaxation of vascular smooth muscle, resulting in vasodilation and reduced blood pressure. The compound also affects the conduction of electrical impulses in the heart, helping to manage arrhythmias. The primary molecular targets are the calcium channels in the cardiovascular system .

Verapamil: The parent compound of norverapamil, also a calcium channel blocker with similar therapeutic uses.

Diltiazem: Another calcium channel blocker used to treat hypertension and angina.

Nifedipine: A dihydropyridine calcium channel blocker used primarily for hypertension.

Uniqueness of this compound: this compound is unique due to its specific metabolic origin from verapamil and its distinct pharmacokinetic properties. It has a longer half-life and different metabolic pathways compared to its parent compound, making it particularly effective in certain therapeutic contexts .

Norverapamil, the N-demethylated metabolite of verapamil, has garnered attention in pharmacological research due to its distinct biological activities, particularly in the context of drug metabolism, cardiovascular effects, and potential therapeutic applications. This article synthesizes findings from diverse studies to provide a comprehensive overview of this compound's biological activity.

This compound is formed through the N-demethylation of verapamil, primarily mediated by cytochrome P450 enzymes. The CYP105D1 enzyme from Streptomyces griseus has been identified as capable of efficiently catalyzing this reaction, achieving a bioconversion rate of 60.16% within 24 hours under optimized conditions . This enzymatic process highlights the potential for biotechnological applications in producing this compound.

Pharmacokinetics

The pharmacokinetics of this compound reveal significant interindividual variability. In a study involving children treated with verapamil for supraventricular tachyarrhythmias, trough plasma levels of this compound averaged 41.7 ng/ml, correlating with the daily dose . The ratio of this compound to verapamil concentrations (N/V ratio) indicated metabolic clearance improved with age, suggesting developmental factors influence drug metabolism .

Cardiovascular Effects

While this compound exhibits less potency than verapamil as a calcium channel blocker, it retains significant biological activity. Research indicates that this compound can modulate cardiac function and may contribute to the therapeutic effects observed with verapamil . In particular, its role in managing supraventricular tachyarrhythmias has been documented, albeit with caution due to its lower efficacy compared to its parent compound.

Antimicrobial Properties

Recent studies have highlighted this compound's potential in combating Mycobacterium tuberculosis. Both verapamil and this compound were shown to inhibit intracellular growth and drug tolerance mechanisms in macrophage-like cells infected with M. tuberculosis. Notably, this compound was effective at lower concentrations than those required for verapamil . This suggests that this compound may serve as a valuable adjunct in tuberculosis treatment regimens.

Clinical Studies and Case Reports

A dose-finding study evaluated the pharmacokinetics of this compound alongside verapamil in participants receiving rifampin. The study found that higher doses of verapamil resulted in increased levels of both compounds, with a notable increase in the AUC (area under the curve) for this compound compared to baseline measurements . The findings support the hypothesis that drug-drug interactions can significantly alter the pharmacokinetic profiles of these compounds.

Adverse Effects and Safety Profile

Adverse reactions associated with this compound are similar to those seen with verapamil but generally occur at lower frequencies. In pediatric populations, common side effects included bradycardia and hypotension, particularly when plasma levels exceeded therapeutic thresholds . Monitoring is essential to mitigate risks associated with elevated plasma concentrations.