Muscarinic M4 Allosteric Modulators to Limit Peripheral Side Effects
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Solution Overview
Problem
Current treatments for neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction, particularly those targeting the M4 receptor, face challenges due to lack of selective agonists and adverse effects from non-selective activation of peripheral muscarinic receptors.
Innovation Solution
Development of compounds that act as positive modulators of the muscarinic acetylcholine receptor M4 by binding to allosteric sites distinct from the orthosteric site, thereby selectively enhancing the receptor's activity without triggering peripheral side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AChE inhibitors are used to increase acetylcholine levels, then therapeutic efficacy is improved, but gastrointestinal side effects and hepatotoxicity increase
Solution Approach 1:
The invention segments the muscarinic receptor family into distinct subtypes (M1-M5) and develops compounds that selectively target specific subtypes, particularly M4, rather than non-selectively inhibiting acetylcholinesterase. This subtype-specific approach allows therapeutic action on central cholinergic hypofunction while avoiding peripheral side effects mediated by other subtypes
Solution Approach 2:
The patent applies local quality by creating compounds with differential affinity for specific muscarinic receptor subtypes. The selective M4 agonists and PAMs are designed to preferentially bind to and modulate M4 receptors in the central nervous system, while having minimal activity at peripheral M2 and M3 receptors that mediate gastrointestinal and cardiac side effects
2Adaptability or versatility
If selective M4 agonists are developed, then therapeutic specificity is improved, but compound selectivity remains insufficient leading to peripheral activation
Solution Approach 1:
The invention uses positive allosteric modulators as intermediaries that bind to a site distinct from the orthosteric acetylcholine binding site. These PAMs enhance the effect of endogenous acetylcholine at M4 receptors without directly activating the receptor, providing a more nuanced and selective modulation that reduces off-target effects compared to direct agonists
Solution Approach 2:
The patent employs parameter changes by modifying molecular structure and pharmacological properties to achieve selective PAM activity. By changing the mode of action from direct agonism to allosteric modulation, the compounds achieve higher functional selectivity for M4 receptors, as evidenced by selectivity ratios greater than 100-fold over other muscarinic subtypes
Data Source
AI summary
Deuterium-labeled 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)piperidines substituted with pyrrolo[3,4-b]pyridin-5-one, furo[3,4-b]pyridin-5(7H)-one, or [1,2,4]triazolo[4,3-a]pyrimidin-3(2H)-one are positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4) and may have use in treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.