Non-Morphinan Kappa Opioid Receptor Antagonists with Rapid Clearance
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Solution Overview
Problem
Current kappa opioid receptor antagonists, such as norBNI, have long durations of action due to depot effects or adaptive plasticity, limiting their therapeutic use due to extended retention in tissues and potential side effects.
Innovation Solution
Development of novel compounds with a different structural framework, such as those described by formula I, which are modular, lack stereogenic centers, and have a clearance rate of less than 12 hours, allowing for safer and more effective therapeutic regimes by selectively antagonizing kappa opioid receptors without prolonged tissue retention.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If current kappa opioid receptor antagonists (such as norBNI) are used, then they provide prolonged therapeutic action, but they exhibit extended retention in tissues leading to potential side effects
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of kappa opioid receptor antagonists to alter their pharmacokinetic properties. Specifically, the invention changes the molecular framework from traditional morphinan-like structures to non-morphinan structures with different clearance rates, achieving a balance between duration of action and tissue retention. The compounds are designed to have clearance rates of less than 12 hours, which reduces prolonged tissue retention and associated side effects while maintaining therapeutic efficacy.
2Duration of action of stationary object
If compounds with longer duration of action are used, then therapeutic coverage is extended, but the risk of prolonged side effects increases
Solution Approach 1:
The patent employs the principle of short-living objects by designing kappa opioid receptor antagonists with limited tissue retention. The compounds are engineered to be cleared from the body within a specific timeframe (clearance rate less than 12 hours), preventing prolonged accumulation and associated harmful effects. This approach allows for adequate therapeutic coverage during the active period while automatically limiting the duration of potential side effects through rapid clearance mechanisms.
3Reliability
If traditional morphinan-like antagonist structures are used, then receptor binding affinity is achieved, but structural complexity and stereogenic centers increase
Solution Approach 1:
The patent applies segmentation by dividing the traditional morphinan structure into separate functional components. Instead of using the complex fused ring system with multiple stereogenic centers, the invention segments the receptor-binding pharmacophore into discrete elements that can be independently optimized. This modular approach maintains the essential interactions with the kappa opioid receptor while eliminating unnecessary structural complexity and chiral centers, resulting in simpler molecules with comparable or improved binding affinity.
Data Source
AI summary
The present technology is directed to compounds, compositions, and methods related to non-morphinan-like kappa opioid receptor (KOR) antagonists. The technology is suited to treat addiction, diuresis, depression, post traumatic stress disorder, an eating disorder, panic disorder, social anxiety disorder, general anxiety disorder, obsessive compulsive disorders, excessive or unreasonable specific phobias, and/or other conditions related to anxiety or aversion-reward responses.