Long-Acting K-Opioid Receptor Agonist for Reduced Dosing Frequency
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Solution Overview
Problem
Long-term use of µ-opioid receptor drugs leads to side effects such as tolerance, dependence, and respiratory depression, while non-opioid analgesics have limited efficacy and side effects, and existing K-opioid receptor agonists like Difelikefalin require daily administration due to a short half-life.
Innovation Solution
Development of a long-acting K-opioid receptor agonist, represented by structural formula I, including compounds like D-Phe-AA1-AA2-D-Lys-4-amino-4-piperidinecarboxylic acid-AA3-AA4(R)-AA5, which can be administered less frequently to improve patient compliance and reduce side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Difelikefalin is used as a K-opioid receptor agonist, then pruritus relief and postoperative analgesia are achieved, but the short half-life requires daily administration reducing patient compliance
Solution Approach 1:
The patent modifies the chemical structure of Difelikefalin by introducing a fatty acid amide group at the N-terminus, changing the pharmacokinetic parameters of the molecule. This structural modification extends the half-life from hours to days, transforming the dosing frequency from daily to weekly or less frequent administration while maintaining analgesic efficacy
Solution Approach 2:
The invention creates a hybrid molecule combining the peptide structure of Difelikefalin with a fatty acid amide moiety. This composite structure integrates the analgesic properties of the original peptide with the long-lasting characteristics of fatty acid amides, achieving both effective pain relief and improved patient compliance
2Reliability
If µ-opioid receptor drugs are used for analgesia, then pain relief is achieved, but long-term use leads to tolerance, dependence, and respiratory depression
Solution Approach 1:
The patent extracts the analgesic function from the µ-opioid receptor pathway and relocates it to the κ-opioid receptor pathway. By selectingivity activating κ-receptors instead of µ-receptors, the invention separates the desired pain-relieving effect from the harmful side effects associated with µ-receptor activation, such as respiratory depression and dependence
Solution Approach 2:
The κ-opioid receptor acts as an intermediary target that can mediate analgesic effects without triggering the adverse responses associated with µ-receptor activation. The patent uses κ-agonists as intermediary substances that achieve the same therapeutic goal (pain relief) through a different physiological pathway, avoiding the harmful intermediaries (side effects) produced by conventional opioids
Data Source
AI summary
Provided is a long-acting K-opioid receptor agonist. The long-acting K-opioid receptor agonist is used for preparing a pharmaceutical composition for treating diseases, the pharmaceutical composition being used for relieving moderate to severe patient itchiness and postoperative analgesia.