Methylphenidate Analogues Targeting Alpha-Synuclein Synapsin III
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Solution Overview
Problem
Current treatments for Parkinson's disease, such as methylphenidate (MPH), do not effectively target the alpha-synuclein/Synapsin III interplay, which is crucial for neuronal degeneration and motor impairment in Parkinson's disease, and may have limited efficacy in reducing alpha-synuclein aggregation and improving motor symptoms.
Innovation Solution
Development of methylphenidate analogues, particularly the threo isomers with structural modifications like the p-tolyl group, that enhance interaction with Synapsin III, reducing alpha-synuclein aggregation and stimulating functional interaction, thereby offering disease-modifying effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If methylphenidate (MPH) is used to treat Parkinson's disease, then motor symptoms are temporarily alleviated through dopamine reuptake inhibition, but the treatment does not effectively target alpha-synuclein aggregation and neuronal degeneration
Solution Approach 1:
The patent modifies the chemical structure of methylphenidate by changing parameters such as the aromatic ring substitution (adding p-tolyl group), stereochemistry (selecting threo isomer), and side chain modifications to create analogues that specifically target Synapsin III and alpha-synuclein interaction, thereby improving efficacy in reducing alpha-synuclein aggregation while maintaining dopamine transporter inhibition
Solution Approach 2:
The patent introduces Synapsin III as an intermediary target molecule. The modified methylphenidate analogues work by enhancing the interaction between Synapsin III and alpha-synuclein, using Synapsin III as a mediator to achieve disease-modifying effects that conventional MPH cannot accomplish
2Reliability
If conventional methylphenidate is used, then dopamine reuptake is inhibited providing symptomatic relief, but disease-modifying effects are not achieved due to inability to reduce alpha-synuclein aggregation
Solution Approach 1:
The patent applies systematic parameter changes to the methylphenidate molecular structure, including stereochemical configuration (threo isomer selection), aromatic ring modifications (p-tolyl group addition), and side chain variations, to achieve disease-modifying effects while maintaining feasibility of synthesis through established organic chemistry methods
3Reliability
If structural modifications are made to enhance Synapsin III interaction, then alpha-synuclein aggregation is reduced and disease-modifying effects are achieved, but molecular complexity increases
Solution Approach 1:
The patent applies local quality modifications by making specific, targeted changes to particular regions of the methylphenidate molecule (such as adding substituents at specific positions on the aromatic ring or modifying specific side chains) rather than completely redesigning the entire molecular structure, thus enhancing Synapsin III interaction while limiting overall molecular complexity increase
Data Source
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AI summary
The present invention describes compounds of formula (A) for use as Parkinson's disease modifying-agents, said formula (A). Surprisingly it has been found that the compounds of the invention can significantly reduce alpha-synuclein aggregation and stimulate the functional interaction between alpha-synuclein and Synapsin III.