Polymer-Conjugated NMDAR Antagonists for Peripheral NMDAR Targeting
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Solution Overview
Problem
Existing NMDAR antagonist drugs that cross the blood-brain barrier (BBB) cause central nervous system (CNS) effects, including psychoactive and toxic effects, which hinder their development as therapeutic drugs for peripheral diseases due to the prominent CNS effects.
Innovation Solution
Development of NMDAR antagonist polymer conjugates (PDCs) with modified polymer structures to impede or modulate the crossing of the BBB and intestinal barrier (IB), allowing preferential targeting of peripheral NMDARs and reducing CNS side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NMDAR antagonist drugs are used to target peripheral NMDARs, then peripheral therapeutic effects are achieved, but CNS side effects including psychoactive and toxic effects occur
Solution Approach 1:
The patent segments the drug delivery system by using polymer conjugates that selectively target peripheral NMDARs while excluding CNS penetration. The polymer-drug conjugate structure separates the peripheral therapeutic function from CNS exposure, allowing peripheral tissue targeting without brain penetration, thus eliminating psychoactive and toxic CNS side effects while maintaining peripheral efficacy.
Solution Approach 2:
The invention applies local quality by designing polymer conjugates with specific physical and chemical properties that enable selective accumulation in peripheral tissues. The polymer structure provides localized delivery to peripheral NMDAR-expressing tissues while preventing CNS penetration, creating a spatially selective therapeutic effect that concentrates the drug where needed without affecting the CNS.
2Reliability
If NMDAR antagonist drugs cross the blood-brain barrier, then CNS NMDARs are blocked, but psychoactive and dissociative effects are produced
Solution Approach 1:
The patent extracts the harmful CNS penetration capability from the drug system by using polymer conjugates that are deliberately designed not to cross the blood-brain barrier. The polymer structure acts as a barrier that removes the drug from CNS access while maintaining peripheral availability, thus separating the beneficial peripheral NMDAR blocking activity from the harmful psychoactive effects caused by CNS penetration.
3Reliability
If polymer conjugates are designed to impede BBB crossing, then peripheral targeting is improved, but drug absorption and distribution are modified
Solution Approach 1:
The invention applies parameter changes by systematically varying polymer characteristics such as molecular weight, hydrophobicity, and chain length to optimize the balance between peripheral targeting and pharmacokinetic properties. These parameter adjustments allow fine-tuning of BBB penetration resistance while maintaining adequate drug absorption and distribution to peripheral tissues, achieving selective peripheral action without compromising overall pharmacokinetic viability.
Data Source
AI summary
The present invention discloses novel molecules consisting of N-methyl-D-aspartate receptor (NMDAR) antagonists-polymer conjugates having a general structure D-(X-Poly-T)n, wherein D is an high affinity, i.e., (+)-, (−)-, or (±)-dizocilpine, or a low affinity, i.e., (+)-, (−)-, or (±)-methadone, CNS active NMDAR antagonist, n is an integer comprised between 1 and 6. X is a stable (enzymatically and/or hydrolytically under physiological conditions) linker comprising a covalent bond or a chain of atoms that covalently attaches a small molecule NMDAR antagonist drug moiety to the Poly derivative. Poly is a covalently bonded chain of repeating monomer units that form a polymer or an oligomer backbone of synthetic or natural origin. T, if present, is either another molecule of D, or a terminal group of Poly, represented by any suitable chemical group which, depending upon preference, is unreactive or reactive with other chemical moieties, or has a targeting property.