Azabicyclohexane Dopamine D3 Modulators for Selective Receptor Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current compounds for modulating dopamine D3 receptors are limited in their ability to effectively treat conditions such as drug dependency and antipsychotic disorders without causing significant extrapyramidal side effects.
Innovation Solution
Development of novel compounds of formula (I) and their salts, which exhibit high affinity for dopamine D3 receptors, specifically designed to act as modulators, potentially offering selective antagonism or inhibition to reduce side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current compounds are used to modulate dopamine D3 receptors, then treatment of drug dependency and antipsychotic disorders can be achieved, but significant extrapyramidal side effects occur
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (azabicyclo[3.1.0]hexane core with particular substituent patterns at positions R1, R2, and Y) that confer selective affinity for D3 receptors. This localized structural optimization enables the compound to interact preferentially with D3 receptors over D2 receptors, achieving therapeutic effects with reduced extrapyramidal side effects
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters including the substituent groups (halogen, hydroxy, cyano, alkyl, alkoxy, alkanoyl, SF5), the linker type (X = -CH2-, -O-, or -S-), and the aromatic/heteroaromatic group Y to optimize the balance between D3 receptor affinity and D2 receptor selectivity. This parametric optimization resolves the contradiction by tuning molecular properties to achieve therapeutic efficacy while minimizing harmful side effects
2Reliability
If compounds with high affinity for dopamine receptors are used, then treatment effectiveness is improved, but selectivity between D3 and D2 receptors decreases leading to more side effects
Solution Approach 1:
The patent achieves local quality by incorporating specific structural elements (the azabicyclo[3.1.0]hexane core with defined substitution patterns) that create a unique molecular recognition profile. This localized structural design enables high affinity for D3 receptors while maintaining selectivity against D2 receptors, resolving the contradiction between affinity and selectivity
Solution Approach 2:
The patent applies asymmetry through the chiral centers in the azabicyclo[3.1.0]hexane structure and the asymmetric substitution patterns. This asymmetric molecular architecture provides stereoselective interaction with the D3 receptor binding site, enhancing both affinity and selectivity simultaneously by exploiting the asymmetric nature of the receptor-ligand interaction
Data Source
AI summary
The present invention relates to novel compounds of formula (I) or a salt thereof: Formula (I), wherein: p is 0, 1, 2, 3, 4 or 5; R1 is independently selected from a group consisting of: halogen, hydroxy, cyano, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C1-4alkanoyl and SF5; n is 3 or 4; R2 is hydrogen or C1-4alkyl; n is 2 or 3; X is -CH2-, -O- or -S-; Z may be -CH- or N; A is a group P or P1, wherein P is Formula (Ia) and P1 is Formula (Ib); and Y is hydrogen, -OH, C1-4alkyl, haloC1-4alkyl, phenyl or a heteroaromatic group, wherein the phenyl and the heteroaromatic group are optionally substituted by one or two substituents selected from a group consisting of C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloC1-4alkoxy; processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D3 receptors, e.g. to treat substace related disorders, as antipsychotic agents premature ejaculation or cognition impairment.