1-Benzylquinoxalin-2(1H)-one Analogs as M1 Allosteric Modulators
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Solution Overview
Problem
There is a scarcity of potent, efficacious, and selective positive allosteric modulators of the M1 muscarinic acetylcholine receptor that are effective in treating neurological and psychiatric disorders associated with cholinergic activity, due to the high conservation of the orthosteric ACh binding site, leading to adverse effects and lack of selectivity in existing compounds.
Innovation Solution
Development of substituted 1-benzylquinoxalin-2(1H)-one analogs that act as positive allosteric modulators of the M1 muscarinic acetylcholine receptor, potentiating its activity without directly activating it, thereby enhancing cognitive function and treating disorders like Alzheimer's disease and schizophrenia.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If orthosteric ACh binding site is targeted for M1 receptor activation, then M1 receptor activity is enhanced, but selectivity is reduced and adverse effects occur due to high conservation of the binding site
Solution Approach 1:
The patent introduces an allosteric modulator as an intermediary that indirectly enhances M1 receptor activity by binding to a distal site rather than the conserved orthosteric ACh binding site. This intermediary approach allows modulation of receptor function while avoiding direct competition at the highly conserved orthosteric site, thereby maintaining selectivity and reducing adverse effects associated with direct orthosteric agonism.
Solution Approach 2:
The patent transitions from targeting the orthosteric binding site (one dimension) to targeting an allosteric site at a different spatial location (another dimension) on the M1 receptor. This dimensional shift in binding site selection allows for selective modulation of M1 receptor activity while avoiding the cross-reactivity issues inherent in orthosteric site targeting due to its high conservation across receptor subtypes.
2Object-affected harmful factors
If positive allosteric modulators are developed to enhance M1 selectivity, then adverse effects are reduced, but potency and efficacy are insufficient in existing compounds
Solution Approach 1:
The patent employs parameter changes in the chemical structure of the allosteric modulator, specifically varying substituents at positions R1-R10 on the core bicyclic heteroaromatic framework. These structural parameter modifications are optimized to simultaneously enhance binding affinity (potency) and functional efficacy at the M1 allosteric site while maintaining selectivity, thereby resolving the trade-off between reduced adverse effects and insufficient potency/efficacy in existing compounds.
Solution Approach 2:
The patent creates composite molecular structures combining a core bicyclic heteroaromatic framework with various functional substituents (R1-R10 groups including aryl, heteroaryl, alkyl, and heterocyclic moieties). This composite structural approach allows optimization of multiple properties simultaneously - the core structure provides allosteric binding while substituents fine-tune potency, efficacy, and selectivity, overcoming the limitations of simpler allosteric modulator structures.
Data Source
AI summary
The invention relates to substituted 1-benzylquinoxalin-2(1H)-one analogs, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M1 (mAChR M1); methods for making the compounds; pharmaceutical compositions; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. Exemplary 1-benzylquinoxalin-2(1H)-one compounds include compounds of the following formula: