M4 Receptor Modulators via Local Quality and Intermediaries
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Solution Overview
Problem
Current treatments for cognitive impairments associated with Alzheimer's disease and schizophrenia, such as those involving acetylcholinesterase inhibitors, suffer from significant side effects like gastrointestinal issues and hepatotoxicity, and have not effectively targeted the muscarinic acetylcholine receptor M4 subtype, which is crucial for cognitive processing and psychotic disorders.
Innovation Solution
Development of compounds that act as positive allosteric modulators of the muscarinic acetylcholine receptor M4, which can selectively enhance receptor activity without activating peripheral receptors, thereby reducing side effects and improving therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If acetylcholinesterase inhibitors are used to increase acetylcholine levels, then cognitive function is improved, but gastrointestinal side effects and hepatotoxicity occur
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (pyrazolo-thieno-pyridazin core with various substituents) that confer selective affinity for M4 receptors over other muscarinic subtypes. This structural differentiation enables the drug to act locally on M4 receptors in the brain while sparing peripheral M2 and M3 receptors, thereby improving cognitive function without causing gastrointestinal side effects or hepatotoxicity associated with non-selective cholinergic agents
Solution Approach 2:
The patent uses positive allosteric modulators as intermediaries that indirectly enhance M4 receptor activity rather than directly activating it. These modulators bind to allosteric sites on the M4 receptor and potentiate the effect of endogenous acetylcholine, providing a more nuanced and selective mechanism of action that achieves therapeutic benefits while minimizing off-target effects on other receptor subtypes
2Reliability
If selective M4 agonists are developed to target cognitive processing, then therapeutic efficacy for psychotic disorders is improved, but selectivity for M4 receptor subtype is difficult to achieve
Solution Approach 1:
The patent employs local quality by introducing specific substituent patterns on the pyrazolo-thieno-pyridazin core structure that create a unique molecular recognition profile for M4 receptors. Variations in substituents at specific positions (such as R1-R6 groups) fine-tune the compound's affinity and selectivity for M4 over other muscarinic subtypes, enabling highly selective M4 modulation for treating psychotic disorders without cross-reactivity
Solution Approach 2:
The patent utilizes parameter changes by systematically varying molecular parameters such as substituent types, positions, and stereochemistry on the core structure to optimize M4 selectivity. By adjusting these chemical parameters, the invention achieves compounds with enhanced affinity for M4 receptors while maintaining or improving selectivity ratios compared to other muscarinic subtypes, thereby resolving the challenge of developing selective M4 agonists
Data Source
AI summary
In one aspect, the invention relates to substituted pyrazolo[3′,4′:4,5]thieno[2,3-c]pyridazine-3-amine analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.