VMAT2-Selective N-Phenylalkyl Amphetamine Derivatives
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Solution Overview
Problem
Current treatments for central nervous system disorders, eating disorders, and substance use disorders often fail to effectively target the vesicular monoamine transporter-2 (VMAT2), leading to inadequate modulation of dopamine, norepinephrine, and serotonin release, which can result in incomplete therapeutic responses and psychostimulant effects.
Innovation Solution
Development of N-phenylalkyl amphetamine derivatives and pharmaceutical compositions that selectively inhibit VMAT2, reducing the psychostimulant effects and abuse potential of drugs like methamphetamine while modulating neurotransmitter release and uptake, thereby providing a novel treatment approach for these disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used to modulate neurotransmitter release and uptake, then therapeutic response is achieved, but psychostimulant effects and abuse potential occur
Solution Approach 1:
The patent applies parameter changes by developing compounds with specific molecular structures (N-phenyl-N-(1-phenylpropan-2-yl)propan-1-amine derivatives) that selectively target VMAT2 with optimized binding affinity. This structural parameter optimization enables selective inhibition of vesicular monoamine transport without activating psychostimulant pathways, thereby achieving therapeutic effects while minimizing abuse potential
Solution Approach 2:
The patent introduces VMAT2-selective compounds as intermediary substances that mediate neurotransmitter storage modulation. These compounds act as selective intermediaries between the therapeutic goal (neurotransmitter modulation) and the harmful outcome (psychostimulant effects), blocking VMAT2-mediated storage while avoiding activation of other neurotransmitter transporters associated with psychostimulant effects
2Object-generated harmful factors
If VMAT2 is inhibited to reduce psychostimulant effects, then abuse potential is reduced, but neurotransmitter storage and release modulation may be insufficient
Solution Approach 1:
The patent applies local quality by designing compounds with specific substituent patterns (R1, R2, R3, R4 groups) that create localized molecular features for selective VMAT2 binding. The aryl groups with specific substituents (methoxy, halogen, alkyl) provide localized interaction points that enhance VMAT2 selectivity while maintaining adequate neurotransmitter storage modulation for therapeutic efficacy
Solution Approach 2:
The patent employs dynamics by developing a series of analogues with varying substituent configurations that allow optimization of the balance between VMAT2 inhibition strength and therapeutic efficacy. The dynamic structural variations enable fine-tuning of compound properties to achieve sufficient neurotransmitter modulation while maintaining low abuse potential
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds demonstrate high affinity and selectivity for VMAT2, significantly reducing methamphetamine-stimulated locomotor activity and potential abuse, offering a promising therapeutic option for central nervous system disorders, eating disorders, and substance use disorders by modulating neurotransmitter storage and release.
Implementation Method 1
Vesicles also serve the role of protecting the neurotransmitter molecules from metabolic breakdown. One transport site on the vesicle membrane is the vesicular monoamine transporter-2 (VMAT2), whose role is to transport transmitters from the cytosol into the synaptic vesicle.
Data Source
AI summary
The present invention relates to methods of treatment of a disease or pathology of the central nervous system, an eating disorder, or substance use disorder, drug dependence/abuse and withdrawal therefrom comprising administering at least one N-phenylalkyl amphetamine derivative and pharmaceutical compositions comprising at least one N-phenylalkyl amphetamine derivative to an individual in need thereof.