Morphinan Derivatives Targeting Peripheral Opioid Receptors
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Solution Overview
Problem
Current analgesics for pain management often have limitations, including central penetration leading to undesirable side effects and inadequate targeting of peripheral opioid receptors, necessitating the development of compounds that effectively modulate opioid receptors for both central and peripheral pain relief without severe side effects.
Innovation Solution
Development of novel morphinan analogs represented by Formulae I-VII, which act as modulators of μ, δ, κ, and ORL-1 opioid receptors, offering agonist or antagonist activity to treat pain, addiction, and other disorders by administering these compounds to achieve therapeutic effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If centrally penetrating opioid agonists are used to treat pain, then analgesic efficacy is improved, but sedative and psychotomimetic side effects increase
Solution Approach 1:
The patent applies local quality by designing opioids with selective affinity for peripheral opioid receptors versus central receptors. The compounds are engineered to have different binding characteristics at peripheral versus central sites, allowing preferential action at peripheral locations while minimizing central penetration and associated side effects.
Solution Approach 2:
The patent uses peripheral opioid receptors as intermediaries to achieve analgesia without direct central nervous system activation. The compounds act as mediators that transmit analgesic effects through peripheral receptor engagement, bypassing the need for central penetration that causes sedative and psychotomimetic effects.
2Object-affected harmful factors
If peripherally restricted opioid compounds are used to reduce central side effects, then sedative and psychotomimetic effects are reduced, but central analgesic efficacy is decreased
Solution Approach 1:
The patent applies universality by designing compounds that can effectively treat both peripheral and central pain mechanisms. The opioids are engineered to address multiple pain types (neuropathic, inflammatory, nociceptive) through a single agent that acts on peripheral receptors while maintaining sufficient central activity for comprehensive analgesia.
Solution Approach 2:
The patent uses parameter changes by modifying molecular structure to optimize the balance between peripheral selectivity and central penetration. Specific structural parameters (substituents, ring systems, stereochemistry) are adjusted to tune receptor affinity and tissue distribution, achieving the optimal compromise between reducing central side effects and maintaining analgesic efficacy.
3Adaptability or versatility
If non-selective opioid agonists are used to target multiple receptor subtypes, then broad analgesic coverage is achieved, but specificity for desired therapeutic effects is reduced
Solution Approach 1:
The patent applies segmentation by dividing opioid receptor targeting into distinct functional components. The compounds are designed to selectively engage specific receptor subtypes (mu, delta, kappa) or specific locations (peripheral versus central), creating specialized agents rather than broad-spectrum non-selective agonists. This segmented approach allows precise control over which receptors are activated.
Solution Approach 2:
The patent applies inversion by reversing the traditional approach of using non-selective agonists and instead employing selective agents. Rather than starting with broad coverage and accepting side effects, the design begins with high selectivity for specific receptors or locations, then expands coverage through rational drug design and combination strategies.
Data Source
AI summary
The application is directed to compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, R4, and Z are defined as set forth in the specification. In certain embodiments, the invention is also directed to compounds of Formula II-VII and the pharmaceutically acceptable salts and solvates thereof. The invention is also directed to use of compounds of Formula I to VII, and the pharmaceutically acceptable salts and solvates thereof, to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the invention are especially useful for treating pain.