Diphenethylamine Derivatives as KOR Partial Agonists
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Solution Overview
Problem
Current opioid analgesics primarily acting on μ (MOR) receptors face limitations due to adverse effects, tolerance, and addictive potential, while KOR agonists have dose-limiting neuropsychiatric side effects and limited therapeutic utility.
Innovation Solution
Development of novel N-cyclopentylmethyl, N-cyclohexylmethyl, or N-benzyl substituted diphenethylamine derivatives with enhanced binding affinity and antinociceptive potency as KOR partial agonists, which exhibit higher efficacy than full KOR agonists like HS665 and U50,488.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If MOR agonists are used for analgesia, then pain relief is achieved, but adverse effects such as respiratory depression, nausea, sedation, and addictive potential occur
Solution Approach 1:
The invention extracts and isolates the analgesic effect from the harmful effects by selectively targeting KOR receptors instead of MOR receptors. The diphenethylamine derivatives are designed to bind specifically to KOR while avoiding MOR activation, thereby separating the beneficial analgesic/anti-pruritic effects from the harmful respiratory depression, nausea, and addiction associated with MOR agonists
Solution Approach 2:
The patent applies local quality by creating compounds with specific molecular structures (N-cyclopentylmethyl, N-cyclohexylmethyl, or N-benzyl substituted diphenethylamine derivatives with specific hydroxy group positions) that are tailored to interact with specific KOR receptor sites, achieving selective activation that produces desired effects without triggering adverse MOR-mediated responses
2Reliability
If KOR agonists are used for analgesia and anti-pruritic effects, then beneficial actions are achieved, but dose-limiting neuropsychiatric side effects occur
Solution Approach 1:
The invention employs partial agonism at KOR receptors, where the diphenethylamine derivatives activate KOR to produce analgesic and anti-pruritic effects but with a ceiling effect that prevents excessive activation and associated neuropsychiatric side effects. This partial activation strategy achieves therapeutic benefit while limiting adverse outcomes
3Power
If full KOR agonists are used, then high analgesic potency is achieved, but neuropsychiatric adverse effects increase
Solution Approach 1:
The patent utilizes partial agonism where the compounds produce sub-maximal activation of KOR receptors compared to full agonists like HS665 and U50,488. This partial activation maintains high antinociceptive potency through optimized molecular structure while avoiding the excessive receptor activation that leads to dysphoria and other neuropsychiatric adverse effects
Data Source
AI summary
Diphenethylamine derivatives for use as highly active analgesics, diuretics, anxiolytics, for the treatment of neurodegenerative, psychiatric and neuropsychiatric disorders, and also as anti-itch, anti-addiction, anti-inflammatory, anti-obesity, anti-epileptic, anti-convulsant, anti-seizure, anti-stress, anti-psychotic and anti-depressant medications and their pharmaceutically acceptable salts and easily accessible derivatives thereof (e.g. esters, ethers, amides), processes for their preparation and their application in the manufacture of pharmaceutical products.