Diazaspiro Undecane Analgesics for Multimodal Pain Management
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Solution Overview
Problem
Current pain management therapies, particularly opioid agonists, are limited by their efficacy, safety ratio, and side effects, especially in chronic pain conditions, and there is a need for alternative compounds with improved pharmacological activity that can effectively target both mu-opioid and sigma-1 receptors to provide enhanced analgesia with reduced adverse effects.
Innovation Solution
Development of diazaspiro undecane derivatives that act as dual ligands, binding to both the mu-opioid receptor and the sigma-1 receptor, offering a multimodal analgesic approach that synergistically enhances opioid analgesia while minimizing side effects by combining sigma-1 receptor antagonism and mu-opioid receptor agonism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If MOR agonists are administered to treat pain, then analgesic efficacy is improved, but side effects such as constipation, respiratory depression, tolerance, and physical dependence worsen
Solution Approach 1:
The patent combines two distinct pharmacological mechanisms into a single compound: mu-opioid receptor agonism for analgesia and sigma-1 receptor antagonism to reduce side effects and prevent tolerance. This merging allows the compound to provide effective pain relief while simultaneously mitigating the harmful effects associated with traditional MOR agonists alone.
Solution Approach 2:
The dual-action compound serves multiple functions: it acts as a MOR agonist to provide analgesia, while simultaneously functioning as a sigma-1 receptor antagonist to reduce side effects, prevent tolerance development, and enhance overall therapeutic efficacy. This multi-functionality addresses both the beneficial and harmful aspects of opioid therapy within a single agent.
2Duration of action of moving object
If MOR agonists are used for chronic pain treatment, then acute pain relief is achieved, but effectiveness diminishes due to MOR down-regulation and tolerance
Solution Approach 1:
The sigma-1 receptor antagonism component acts in advance to prevent the development of tolerance and MOR down-regulation that typically occur with chronic MOR agonist use. By blocking sigma-1 receptors, the compound preemptively counteracts the mechanisms that lead to diminished effectiveness, thereby maintaining reliable analgesia over extended treatment periods.
Solution Approach 2:
The compound merges MOR agonism for immediate analgesia with sigma-1 receptor antagonism to prevent tolerance development over time. This combination allows the treatment to remain effective throughout chronic use by simultaneously providing pain relief and blocking the adaptive changes that would otherwise reduce efficacy.
3Reliability
If higher doses of MOR agonists are administered to overcome tolerance, then analgesic effect is maintained, but side effects become unacceptable
Solution Approach 1:
The compound combines MOR agonism with sigma-1 receptor antagonism in a single molecule, allowing maintenance of analgesic efficacy without requiring dose escalation. The sigma-1 antagonism component prevents tolerance development, thereby avoiding the need to increase MOR agonist doses and the associated increase in side effects.
Solution Approach 2:
The invention changes the pharmacological parameters by introducing sigma-1 receptor antagonism alongside MOR agonism. This parameter change alters the dose-response relationship, allowing effective pain relief at lower doses that do not produce unacceptable side effects, thereby improving the therapeutic index.
4Adaptability or versatility
If multiple separate medications are used to address different pain mechanisms, then comprehensive pain management is achieved, but drug interactions and complexity increase
Solution Approach 1:
The patent merges two separate pharmacological mechanisms (MOR agonism and sigma-1 receptor antagonism) into a single compound. This consolidation provides comprehensive pain management coverage while eliminating the need for multiple separate medications, thereby reducing regimen complexity and potential drug-drug interactions.
Solution Approach 2:
The dual-action compound serves as a universal agent that addresses multiple pain mechanisms simultaneously. By incorporating both MOR agonism for analgesia and sigma-1 receptor antagonism for enhanced efficacy and reduced tolerance, a single medication replaces what would otherwise require multiple separate drugs, simplifying the treatment regimen.
Data Source
AI summary
The present invention relates to compounds having dual pharmacological activity towards both the sigma (σ) receptor, and the μ-opioid receptor and more particularly to diazaspiro undecane compounds having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain. (formula 1) wherein Y is (formula 2) or (formula 3) • n is 1 or 2; • q is 1, 2, 3, 4, 5 or 6; • X is a bond, -C(O)O-, -C(0)NR 8-, -C(O)-, -0- or -C(R 4R 4.)-; • R 1is C(0)R 5or S(O) 2R 5.