Cyclohexane Derivatives for Dopamine Receptor Selectivity
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Solution Overview
Problem
Current compounds targeting dopamine D3 and D2 receptors lack selectivity and often result in undesirable side effects due to massive receptor blockade, such as extrapyramidal symptoms and cognitive disturbances, limiting their therapeutic utility in treating neuropsychiatric and neurodegenerative disorders.
Innovation Solution
Development of cyclohexane derivatives with a (thio)carbamoyl side chain that exhibit high affinity for D3 receptors and moderate to high affinity for D2 receptors, maintaining a 5 to 200-fold higher D3 affinity, thereby providing dual receptor functional antagonism with reduced side effects by preferentially targeting D3 and D2 receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds with high affinity for both D3 and D2 receptors are used, then dual receptor functional antagonism is achieved, but side effects such as extrapyramidal symptoms and cognitive disturbances occur due to massive D2 receptor blockade
Solution Approach 1:
The patent applies local quality by designing compounds with differential affinity profiles for different receptor subtypes. The cyclohexane derivatives with (thio)carbamoyl side chains exhibit high affinity for D3 receptors and moderate to high affinity for D2 receptors, creating a localized effect where D3 receptors are preferentially targeted while D2 receptors receive partial agonism or weaker antagonism, thereby reducing side effects while maintaining therapeutic efficacy
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure parameters of the compounds - specifically introducing (thio)carbamoyl side chains on cyclohexane derivatives with specific substituent patterns (R1 and R2 groups). These structural parameter changes result in altered receptor binding characteristics, achieving the desired affinity profile with 5 to 200 fold higher D3 affinity compared to D2 affinity
2Object-affected harmful factors
If selective D3 receptor antagonists are used, then side effects are reduced, but therapeutic efficacy is limited due to insufficient D2 receptor modulation
Solution Approach 1:
The patent applies universality by designing compounds that can interact with multiple receptor subtypes (both D3 and D2 dopamine receptors) through a single molecular structure. The cyclohexane derivatives with (thio)carbamoyl side chains possess dual functionality, enabling them to modulate both D3 and D2 receptors simultaneously, thereby achieving comprehensive therapeutic effects while maintaining selectivity
3Measurement precision
If compounds with high D3 affinity are developed, then selectivity over D2 receptors is improved, but the ability to modulate both receptors simultaneously is lost
Solution Approach 1:
The patent applies partial action by designing compounds that exert stronger effects on D3 receptors while maintaining partial activity on D2 receptors. The (thio)carbamoyl-cyclohexane derivatives achieve approximately 5 to 200 fold higher affinity for D3 receptors compared to D2 receptors, allowing preferential D3 modulation while retaining sufficient D2 interaction for comprehensive therapeutic benefit
Data Source
AI summary
The present invention relates to new D3 and D2 dopamine receptor subtype preferring ligands of formula (I):wherein R1 and R2 represent independently a substituent selected from hydrogen, alkyl, aryl, cycloalkyl, aroyl, or R1 and R2 may form a heterocyclic ring with the adjacent nitrogen atom; X represents an oxygen or sulphur atom; n is an integer of from 1 to 2, and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof, to the processes for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of a condition which requires modulation of dopamine receptors.