2-azaspiro[3.4]octane M4 agonists for psychosis
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Solution Overview
Problem
Current antipsychotic drugs have limited efficacy and severe side effects due to their primary action on dopamine D2 receptors, and existing M4 receptor agonists like xanomeline cause cholinergic side effects, necessitating the development of M4 selective agonists that can effectively treat psychosis without these drawbacks.
Innovation Solution
Development of novel 2-azaspiro[3.4]octane compounds that act as selective M4 receptor agonists, specifically designed to target the M4 receptor in the striatum to regulate dopamine signaling without activating M2 and M3 receptors, thereby reducing side effects associated with cholinergic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current antipsychotic drugs act on dopamine D2 receptors, then psychosis treatment is achieved, but severe side effects occur
Solution Approach 1:
The patent extracts and isolates the M4 receptor agonist activity from the broader dopamine receptor targeting approach. By specifically designing compounds that selectively activate M4 receptors rather than blocking D2 receptors, the invention separates the therapeutic antipsychotic effect from the harmful side effects associated with D2 blockade, thereby treating psychosis while avoiding movement disorders and metabolic syndrome
Solution Approach 2:
The patent applies local quality by creating compounds with selective affinity for M4 receptors in the striatum. The chemical structures are designed to specifically interact with M4 receptor binding sites while having minimal interaction with other muscarinic or dopamine receptors, thereby localizing the pharmacological effect to the desired target and reducing systemic side effects
2Reliability
If xanomeline activates all muscarinic receptor subtypes, then antipsychotic efficacy is achieved, but cholinergic side effects occur
Solution Approach 1:
The patent segments the muscarinic receptor family into distinct subtypes (M1-M5) and specifically targets only the M4 subtype. By designing compounds with selective M4 agonist activity and minimal activity at M1, M2, M3, and M5 receptors, the invention divides the broad muscarinic activation effect into a focused M4-specific effect, retaining antipsychotic benefits while eliminating cholinergic side effects caused by activation of other subtypes
Solution Approach 2:
The patent applies local quality by creating compounds with selective affinity for M4 receptors. The chemical structures are optimized to specifically interact with M4 receptor binding sites in the striatum while having minimal interaction with other muscarinic receptors, thereby localizing the pharmacological effect to the desired target and reducing systemic cholinergic side effects
Data Source
AI summary
Provided herein are compounds according to Formula (I)or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R5, and R7 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) as well as the use of such compounds as M4 receptor agonists.