Adenosine Analog Blood-Brain Barrier Penetration for Circadian Phase Shifting
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Solution Overview
Problem
Current treatments for jet lag and shift-work disorders are inadequate, as existing clock drugs either have no effect on behavior or require invasive intracerebroventricular injection to penetrate the brain, making them impractical for clinical use.
Innovation Solution
Development of small molecules, specifically adenosine analogs and their related compounds, which can shift the circadian clock phase without the need for brain injection by penetrating the blood-brain barrier, using a chemical screening strategy and Structure-Activity Relationship studies to identify compounds effective in nanomolar ranges.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing clock drugs are used to shift circadian phase, then circadian rhythm modulation is achieved, but the drugs require invasive intracerebroventricular injection to penetrate the brain
Solution Approach 1:
The patent uses adenosine analogs as intermediary compounds that can cross the blood-brain barrier to deliver the circadian phase-shifting effect without requiring direct brain injection. These analogs act as mediators between peripheral administration and central clock modulation, solving the contradiction between efficacy and ease of administration.
Solution Approach 2:
The invention modifies the chemical parameters of adenosine to create analogs with improved pharmacokinetic properties, specifically enhanced ability to cross the blood-brain barrier while maintaining circadian phase-shifting activity. This parameter change enables effective peripheral administration without invasive procedures.
2Reliability
If existing clock drugs are used to shift circadian phase, then circadian rhythm modulation is achieved, but the drugs have no effect on behavior
Solution Approach 1:
The adenosine analogs serve as effective intermediaries that successfully transmit the phase-shifting signal from peripheral administration to central clock mechanisms, producing both molecular and behavioral effects. This intermediary approach resolves the contradiction by ensuring the drug actually reaches and affects the behavioral output of the circadian system.
3Reliability
If adenosine analogs are administered to shift clock phase, then circadian oscillation phase is reversed by 12 hours, but the working concentration was initially high
Solution Approach 1:
The patent systematically optimized the chemical parameters of adenosine analogs to enhance their pharmacokinetic properties, including bioavailability and metabolic stability. These parameter changes reduced the required working concentration from micromolar to nanomolar ranges, resolving the contradiction between efficacy and dosage.
Solution Approach 2:
The invention creates optimized copies of adenosine with improved properties through structural modifications. These analogs replicate the essential function of adenosine in clock modulation while possessing superior pharmacokinetic characteristics that enable lower effective doses.
4Ease of operation
If conventional clock drugs are administered peripherally, then administration is simplified, but the drugs cannot penetrate the blood-brain barrier to affect central clock
Solution Approach 1:
The patent modified key chemical parameters of the adenosine analogs, including lipophilicity and molecular size, to enhance blood-brain barrier penetration while maintaining peripheral administrability. This parameter optimization resolves the contradiction between ease of administration and brain penetration capability.
Data Source
AI summary
The present invention provides a kind of nucleoside analogue compounds, and a composition comprising the compound and pentostatin, their use for modulating circadian rhythm, preferably, for shifting circadian phase, and methods for modulating circadian rhythm, preferably, for shifting circadian phase via the compound or the composition.