Beta-2 Adrenoceptor Allosteric Modulators for Asthma
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Solution Overview
Problem
Current β2-adrenoceptor agonists for asthma and obstructive lung diseases face limitations due to agonist-induced desensitization and non-canonical signaling pathways that promote asthma pathophysiology, necessitating the development of alternative treatment strategies that can effectively modulate β2-adrenoceptor signaling without these drawbacks.
Innovation Solution
Development of allosteric modulators that bind to distinct sites on the β2-adrenoceptor, either augmenting or reducing signaling transduced by orthosteric ligands, using compounds of specific chemical structures to target intermediate conformational states of the receptor, identified through molecular dynamics simulations and site identification by ligand competitive saturation technology.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If β2-adrenoceptor agonists are used to treat asthma and obstructive lung diseases, then bronchodilation and airway smooth muscle relaxation are achieved, but agonist-induced desensitization and non-canonical β2AR signaling occur that promote asthma pathophysiology
Solution Approach 1:
The patent segments the β2AR signaling pathway into canonical (Gs-cAMP) and non-canonical (β-arrestin) pathways by using allosteric modulators that selectively enhance beneficial Gs signaling while preventing harmful β-arrestin recruitment, thereby achieving pathway-specific modulation
Solution Approach 2:
The patent introduces allosteric modulators as intermediary compounds that bind to distinct allosteric sites on β2AR rather than the orthosteric site, enabling indirect modulation of receptor conformation and signaling outcomes without direct orthosteric agonist activation
2Duration of action of moving object
If orthosteric agonists are used to activate β2-adrenoceptors, then airway smooth muscle relaxation occurs, but the therapeutic effect is limited by desensitization
Solution Approach 1:
The patent employs dynamic allosteric modulators that can adaptively regulate β2AR conformational states, allowing the receptor to maintain responsiveness over time by preventing fixed desensitized states while preserving physiological signaling dynamics
3Duration of action of stationary object
If β2-adrenoceptor agonists are administered chronically, then ongoing bronchodilation is achieved, but airway hyperresponsiveness and inflammation are exacerbated
Solution Approach 1:
The patent changes the binding parameters and signaling outcomes by using allosteric modulators with distinct binding kinetics and conformational effects, thereby altering the temporal and spatial parameters of receptor activation to reduce pro-inflammatory signaling during chronic treatment
Data Source
AI summary
The disclosure relates to allosteric modulators of β2-adrenoceptor, pharmaceutical compositions thereof, and use thereof for the treatment of disease.