Polypeptide Compounds for Selective Kappa Opioid Receptor Agonism
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Solution Overview
Problem
Current µ opioid receptor agonists, such as morphine, cause significant side effects like respiratory depression, addiction, and constipation, and existing κ opioid receptor agonists may have limitations in clinical use due to side effects like hypernatremia and limited analgesic efficacy.
Innovation Solution
Development of novel polypeptide compounds containing boric acid structural fragments that act as κ opioid receptor agonists, which are designed to provide better analgesic activity with reduced side effects by reversibly interacting with protein targets.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional μ opioid receptor agonists (morphine, pethidine, etc.) are used for pain relief, then strong analgesic effect is achieved, but respiratory depression, addiction, and constipation occur
Solution Approach 1:
The patent extracts the analgesic function from μ opioid receptors and relocates it to κ opioid receptors. The peptidomimetic compounds are designed to selectively activate κ receptors while avoiding μ receptor activation, thereby extracting the harmful side effects (respiratory depression, addiction) while preserving the beneficial analgesic effect.
Solution Approach 2:
The patent changes the receptor selectivity parameter by designing peptidomimetic compounds with specific structural features (peptide backbone combined with pharmacophoric moieties) that confer high selectivity for κ opioid receptors over μ opioid receptors. This parameter change shifts the side effect profile while maintaining analgesic efficacy.
2Object-generated harmful factors
If κ opioid receptor agonists are used to avoid μ receptor side effects, then respiratory depression and addiction are reduced, but hypernatremia and limited analgesic efficacy occur
Solution Approach 1:
The patent creates composite molecular structures combining peptide backbones (which provide κ receptor selectivity and reduced side effects) with pharmacophoric moieties (which enhance analgesic efficacy). This composite approach integrates the advantages of both natural peptides and synthetic analgesics to overcome the limitations of pure κ agonists.
Solution Approach 2:
The patent optimizes multiple molecular parameters simultaneously: peptide sequence composition, pharmacophore type, and structural configuration, to achieve the desired balance between κ receptor selectivity (reducing side effects) and analgesic potency (improving efficacy).
3Object-generated harmful factors
If large/hydrophilic pharmacophores are used to prevent blood-brain barrier penetration, then central nervous system entry is reduced, but peripheral analgesic effect is limited
Solution Approach 1:
The patent applies local quality by designing molecules with hydrophilic peptide backbones (preventing CNS penetration) combined with specific pharmacophoric moieties (enabling peripheral analgesic activity through inflammation-mediated opioid receptor activation). Different parts of the molecule have different properties optimized for their specific functions.
Data Source
AI summary
The present invention discloses a polypeptide compound, a pharmaceutical composition, and a preparation method and use thereof. The structural formula of the polypeptide compound is shown in general formula (I): Such polypeptide compounds as κ-opioid receptor agonists have the advantages of better activity and the potential to become clinical candidate compounds.