Macrocyclic Tetrapeptides Selective KOR Antagonism
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Solution Overview
Problem
Current therapies for addiction and pain management, particularly targeting opioid receptors, face challenges due to off-target effects and limited ability to selectively target kappa opioid receptors (KOR), leading to undesirable side effects and short duration of action.
Innovation Solution
Development of macrocyclic tetrapeptides, such as cyclo[Phe-D-Pro-Phe-Trp] and its D-Trp isomer, which are designed to modify solubility and pharmacokinetic properties while maintaining pharmacological activity, allowing for selective KOR antagonism and potential oral administration across the blood-brain barrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current opioid therapies are used, then analgesic effects are achieved, but off-target effects and limited selectivity for kappa opioid receptors occur leading to undesirable side effects
Solution Approach 1:
The patent segments the opioid receptor targeting by designing macrocyclic compounds with specific structural features that selectively bind to kappa opioid receptors (KOR) while avoiding other opioid receptor subtypes. The macrocyclic structure with specific amino acid sequences and functional groups enables selective KOR interaction, thereby achieving reliable selectivity without off-target effects.
Solution Approach 2:
The patent applies local quality by modifying specific regions of the macrocyclic structure, particularly at the amino-terminus and through specific amino acid residues (e.g., D-Pro, Trp), to enhance KOR selectivity. These localized structural modifications create specific interaction patterns with KOR that distinguish it from other opioid receptors, eliminating harmful off-target effects.
2Duration of action of moving object
If current opioid therapies are used, then pain management is provided, but duration of action is limited and short
Solution Approach 1:
The patent employs preliminary action by designing macrocyclic compounds with enhanced pharmacokinetic properties that maintain prolonged KOR occupancy and sustained analgesic effects. The macrocyclic structure provides resistance to enzymatic degradation and extended plasma half-life, ensuring prolonged duration of action that reduces the need for frequent re-administration.
3Reliability
If macrocyclic compounds are designed to improve selectivity, then KOR antagonism is enhanced, but solubility and pharmacokinetic properties must be optimized
Solution Approach 1:
The patent applies parameter changes by systematically modifying the macrocyclic structure's physical and chemical parameters, including amino acid composition, side chain length, and functional group placement. These parameter adjustments optimize both KOR selectivity and pharmacokinetic properties such as solubility, metabolic stability, and oral bioavailability, resolving the contradiction between selectivity and manufacturability.
4Reliability
If existing opioid therapies are used, then analgesic effects are achieved, but tolerance and dependence develop with long-term use
Solution Approach 1:
The patent extracts the analgesic efficacy function from traditional opioid therapies that cause tolerance and dependence by selectively targeting kappa opioid receptors instead of mu opioid receptors. The macrocyclic compounds provide analgesic effects through KOR activation while avoiding the reward pathway and dependence mechanisms associated with MOR activation, thereby maintaining efficacy without tolerance or dependence.
Data Source
AI summary
The invention relates to macrocyclic peptides and pharmaceutical compositions thereof. The invention further relates to pharmaceutical compositions for modulating opioid receptor activity.