Ropinirole

Synthetic Routes and Reaction Conditions

Ropinirole can be synthesized through several methods. One common method involves the reduction of a 2-nitrophenyl acetic acid precursor followed by spontaneous cyclization. Another method involves the reductive cyclization of 2-(2’-bromoethyl) β-nitrostyrene using palladium on carbon (Pd/C) as a catalyst .

Industrial Production Methods

In industrial settings, this compound hydrochloride is often prepared by dissolving the compound in solvents such as ethanol, methanol, or ethyl acetate, followed by the addition of Pd/C. The mixture is then reacted to obtain the desired product .

Types of Reactions

Ropinirole undergoes various chemical reactions, including:

Oxidation: this compound can be oxidized to form different metabolites.

Reduction: The reduction of nitro groups to amines is a key step in its synthesis.

Substitution: Halogenation and sulfonation reactions are also involved in its synthesis.

Common Reagents and Conditions

Oxidation: Common oxidizing agents include hydrogen peroxide and potassium permanganate.

Reduction: Catalysts like palladium on carbon (Pd/C) are used for reductive cyclization.

Substitution: Reagents such as p-methylbenzenesulfonyl chloride and pyridine are used in substitution reactions.

Major Products Formed

The major products formed from these reactions include various intermediates that eventually lead to the formation of this compound hydrochloride .

Treatment of Parkinson's Disease

Ropinirole has been extensively studied for its effectiveness in managing Parkinson's disease, particularly in early stages. A significant clinical trial demonstrated that patients treated with this compound showed substantial improvements in motor function as measured by the Unified Parkinson's Disease Rating Scale (UPDRS). In this study, this compound-treated patients had a 24% improvement in UPDRS motor scores compared to a -3% change in the placebo group (p < 0.001) .

Efficacy and Safety Data

• Study Design : A double-blind, placebo-controlled trial involving 241 patients.
• Duration : 12 months.
• Results :
  • 44% of this compound-treated patients completed the study without requiring levodopa therapy compared to 22.4% in the placebo group (odds ratio 2.7; P < .001) .
  • Adverse effects were minimal, primarily related to dopaminergic activity .

Management of Restless Legs Syndrome

This compound is also approved for treating restless legs syndrome. Its mechanism as a dopamine agonist helps alleviate symptoms by enhancing dopaminergic transmission in the central nervous system. Clinical studies have shown that this compound significantly reduces the severity of symptoms and improves sleep quality in affected individuals .

Psychotic Symptoms Induced by this compound

While this compound is effective for various conditions, it has been associated with inducing or exacerbating psychotic symptoms in some patients. For instance, a case study reported a patient who developed acute psychosis after starting this compound for restless legs syndrome. Symptoms resolved rapidly upon discontinuation of the drug, highlighting the need for careful monitoring of psychiatric symptoms during treatment .

Potential Applications Beyond Parkinson's Disease

Recent research has explored additional applications of this compound:

• Emotional Regulation : Studies indicate that this compound may influence emotionality and exhibit anxiolytic and antidepressant-like effects without affecting motor functions or cognition .
• Urease Inhibition : Investigations into the compound's pharmacological properties revealed potential urease inhibitory activity, suggesting its utility in treating conditions related to urease activity .

Data Summary

Ropinirole exerts its effects by selectively stimulating dopamine D2 receptors within the caudate-putamen system in the brain. This stimulation helps to compensate for the dopamine deficiency observed in conditions like Parkinson’s disease. This compound has a high affinity for D2 and D3 receptors, with a higher affinity for D3 receptors .

Structural and Pharmacological Differences

Ropinirole vs. Pramipexole

• Chemical Structure : this compound is a substituted oxindole, whereas pramipexole is a cyclohexyl-thiazoline with a chiral center. Both share an alkylamine group critical for receptor binding .
• Receptor Selectivity : Both target D2/D3 receptors, but structural differences influence pharmacokinetics and side-effect profiles.

This compound vs. Piribedil and Rotigotine

• Piribedil (a non-ergoline agonist with D2/D3 and α2-adrenergic antagonism) demonstrates superior efficacy in early PD compared to this compound IR in network meta-analyses .
• Rotigotine (transdermal patch) offers continuous dopaminergic stimulation but lacks head-to-head comparisons with this compound PR .

Efficacy in Parkinson’s Disease

Early PD

• This compound vs. Levodopa (LD) : A 5-year study (N=268) showed LD provided greater UPDRS motor score improvement (+4 points vs. This compound), but this compound delayed dyskinesia. LD supplementation in this compound groups reduced efficacy gaps .
• This compound IR vs. PR : Both formulations show similar UPDRS motor score improvements (mean reduction: ~4–6 points) .

Advanced PD

• Adjunct Therapy : this compound PR reduced OFF-time by 2.1 hours vs. placebo, outperforming IR in maintaining ON-period stability .
• Comparison with Sumanirole: Sumanirole (D2/D3 agonist) demonstrated non-inferiority to this compound in UPDRS II + III scores (difference: 1.17 points, 90% CI: -0.56–2.89) with comparable tolerability .

Pharmacokinetics and Drug Interactions

• Ciprofloxacin Interaction : Ciprofloxacin increases this compound AUC (1.84x) and Cmax (1.6x) via CYP1A2 inhibition .
• Dose Optimization : Population PK models suggest 8–12 mg/day achieves clinical benefit in early PD, while higher doses (>12 mg) improve OFF-time in advanced PD .
• Renal Impairment: No dose adjustment required for mild-to-moderate renal impairment .

Key Clinical Findings and Controversies

• Early LD Initiation : Studies debate whether delaying LD in favor of this compound sacrifices long-term motor benefits .
• Generic vs. Branded PR : Generic this compound PR showed comparable efficacy but increased gastrointestinal AEs (e.g., 3-hour shorter ON-time without dyskinesia) .
• Antioxidant Activity : this compound exhibits poor antioxidant efficacy compared to ascorbic acid and thiazolidine derivatives .

Ropinirole is a non-ergoline dopamine agonist primarily used in the treatment of Parkinson's disease and Restless Legs Syndrome (RLS). Its biological activity is characterized by its interaction with dopamine receptors, pharmacokinetics, and its effects on various neurological and psychological parameters. This article delves into the detailed biological activity of this compound, supported by data tables and relevant case studies.

This compound exhibits a high affinity for post-synaptic dopamine D2 receptors, which are G-protein-coupled receptors located in the central nervous system. These receptors play a crucial role in modulating neurotransmission and motor control. The activation of D2 receptors by this compound inhibits adenylyl cyclase activity, which decreases cyclic AMP levels, leading to reduced neuronal excitability and modulation of various physiological processes .

Pharmacokinetics

Absorption and Bioavailability:

• This compound is rapidly absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours.
• The absolute bioavailability ranges from 45% to 55%, indicating significant first-pass metabolism .

Distribution:

• The volume of distribution is approximately 7.5 L/kg, with about 40% of the drug bound to plasma proteins .

Metabolism:

• This compound is extensively metabolized in the liver, primarily through N-despropylation and hydroxylation. The major metabolic enzyme involved is CYP1A2 .

Elimination:

• Approximately 88% of a radiolabeled dose is recovered in urine, with less than 10% excreted as unchanged drug .

Neurological Impact

This compound has been shown to improve motor function in various models of Parkinson's disease. Clinical studies indicate that it effectively alleviates symptoms associated with both Parkinson's disease and RLS .

Table 1 summarizes key findings from clinical trials regarding the efficacy of this compound:

Psychological Effects

Recent studies have highlighted this compound's influence on emotional regulation. In animal models, doses ranging from 1 to 10 mg/kg have demonstrated anxiolytic and antidepressant-like effects without significantly impacting locomotion or cognition. These effects are associated with alterations in neurotransmitter receptor phosphorylation patterns in the brain .

Case Studies

• Case Study on Nocturnal Tremors:
  A patient with Parkinson's disease exhibited violent nocturnal tremors unresponsive to standard treatment. The introduction of a this compound patch resulted in significant symptom relief, underscoring its utility beyond daytime symptom management .
• Long-term Efficacy:
  A longitudinal study followed Parkinson's disease patients over five years while on this compound therapy. Results indicated sustained improvement in quality of life metrics and motor function, with manageable side effects .

Basic Research Questions

Q. What experimental design considerations are critical for evaluating the dissolution profile of ropinirole extended-release tablets?

• Methodological Answer : Follow FDA dissolution protocols (e.g., USP Apparatus 2 with sinkers) to ensure tablets remain submerged, reducing variability in release rates . Include sinkers to stabilize tablet positioning, improving RSD values (e.g., RSD <10%) while minimally affecting overall dissolution kinetics. Use HPLC with UV detection (250 nm, L7 column) for quantifying this compound and related impurities .
• Data Reference : Studies show sinkers reduce RSD from 15% to 5% in early dissolution phases without altering cumulative release .

Q. How do researchers validate the purity of this compound hydrochloride in preclinical formulations?

• Methodological Answer : Utilize USP reference standards (e.g., USP this compound Hydrochloride RS) for chromatographic calibration. Employ LC-UV systems (e.g., 4.6-mm × 25-cm column, 1 mL/min flow rate) with system suitability criteria: resolution ≥2.0 between this compound and related compounds (e.g., 3-oxo this compound), and S/N ratio ≥10 . Preclinical studies must adhere to NIH guidelines for reproducibility, including detailed reporting of animal models and statistical methods .

Q. What are the standard pharmacokinetic parameters assessed in early-phase this compound trials?

• Methodological Answer : Focus on bioavailability (AUC, Cmax), elimination half-life (t½), and metabolite profiling. Use validated HPLC-MS methods with SPE extraction (C18 columns, methanol-water eluents) to achieve detection limits of 5 ng/mL in plasma . Compare results against healthy baselines to identify deviations in patients with Parkinson’s disease .

Advanced Research Questions

Q. How can contradictory efficacy data between this compound and newer dopamine agonists (e.g., D-512) be reconciled in preclinical models?

• Methodological Answer : Apply comparative dose-response studies in animal models (e.g., MPTP-induced Parkinsonism) to assess symptom relief duration and neuroprotective effects. Use ANOVA and post-hoc tests to analyze differences in motor function scores and neuronal survival rates . Address variability by standardizing disease progression metrics (e.g., Unified Parkinson’s Disease Rating Scale) and controlling for pharmacokinetic confounders (e.g., blood-brain barrier penetration) .
• Data Reference : D-512 showed 30% greater efficacy in symptom relief and 50% lower dyskinesia incidence compared to this compound in rodent models .

Q. What mechanisms underlie this compound’s potential neuroprotective effects in motor neuron disease (MND)?

• Methodological Answer : Use patient-derived iPSCs differentiated into motor neurons to study axonal integrity and cholesterol synthesis pathways. Perform RNA-seq to identify suppressed genes (e.g., 29 genes linked to cholesterol metabolism) and validate via qPCR . Compare dendritic length and synaptic connectivity in this compound-treated vs. control cells using immunofluorescence and morphometric analysis .

Q. How should researchers design studies to resolve discrepancies in this compound’s long-term tolerability across populations?

• Methodological Answer : Implement longitudinal, double-blind RCTs with stratified randomization by age, disease stage, and genetic biomarkers (e.g., DRD2 polymorphisms). Use mixed-effects models to analyze adverse event rates (e.g., nausea, hypotension) and adjust for covariates like CYP1A2 metabolic activity . Include pre/post-test assessments of non-motor symptoms (e.g., sleep disturbances) to capture holistic tolerability .

Q. What analytical strategies optimize detection of this compound-related impurities in stability studies?

• Methodological Answer : Apply forced degradation (e.g., heat, light, pH extremes) followed by LC-MS/MS to identify degradation products (e.g., 4-[2-(dipropylamino)ethyl]indoline-2,3-dione). Use orthogonal methods (e.g., NMR for structural confirmation) and adhere to ICH Q3B guidelines for reporting thresholds .

Q. Methodological Frameworks for this compound Research

• PICO Framework : For clinical trials, structure questions around Population (e.g., advanced Parkinson’s patients), Intervention (this compound XR), Comparison (placebo/alternative agonists), and Outcome (e.g., UPDRS score change) .
• FINER Criteria : Ensure questions are Feasible (e.g., accessible patient cohorts), Interesting (addressing gaps in neuroprotection mechanisms), Novel (exploring MND applications), Ethical (IRB-approved protocols), and Relevant (aligning with NIH priorities) .