Nitrogen-Containing Heterocycles for 5-HT2A/5-HT2C Selectivity
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Solution Overview
Problem
Current therapeutic agents for neurodegenerative disorders such as Parkinson's disease and dementia-related hallucinations and delusions lack selectivity for serotonin 5-HT2A and 5-HT2C receptors, leading to adverse effects on the cardiovascular system and limited efficacy.
Innovation Solution
Development of novel compounds with serotonin 5-HT2A receptor antagonism and/or inverse agonism and 5-HT2C receptor antagonism and/or inverse agonism, designed to target these receptors specifically, reducing adverse effects and improving therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapeutic agents are used for neurodegenerative disorders, then symptomatic relief is achieved, but adverse effects on the cardiovascular system occur and drug tolerance is limited
Solution Approach 1:
The patent applies local quality by designing the compound to have selective binding affinity for specific serotonin receptors (5-HT2A and 5-HT2C) while avoiding interaction with cardiovascular receptors. The molecular structure is optimized to target specific neural pathways involved in hallucinations and delusions, thereby achieving therapeutic effects without cardiovascular side effects.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure of serotonin receptor ligands to alter selectivity parameters. By adjusting molecular weight, lipophilicity, and functional group composition, the compound achieves enhanced specificity for 5-HT2A and 5-HT2C receptors, reducing off-target effects on the cardiovascular system.
2Reliability
If existing antipsychotic and antidepressant agents are used, then neuropsychiatric symptoms are relieved, but drug tolerance is significantly low due to adverse effects
Solution Approach 1:
The patent applies segmentation by separating the therapeutic function from the adverse effect mechanism. The compound is designed to selectively modulate serotonin receptors involved in hallucinations and delusions (5-HT2A and 5-HT2C) while avoiding receptors mediating cardiovascular and other systemic side effects, thereby improving drug tolerance.
Solution Approach 2:
The patent uses the serotonin receptor system as an intermediary mechanism to achieve therapeutic effects. By targeting specific serotonin receptors that mediate hallucinations and delusions, the compound produces psychiatric benefits while the selective nature of this intermediary pathway avoids activation of other receptor systems that cause adverse effects.
3Object-affected harmful factors
If pimavanserin is used for Parkinson's disease hallucinations and delusions, then cardiovascular side effects are reduced, but dosage is restricted due to significant adverse effects
Solution Approach 1:
The patent applies parameter changes by optimizing the pharmacokinetic properties of the compound, including oral bioavailability, half-life, and metabolic stability. These parameter adjustments enable effective dosing without the restrictions encountered with pimavanserin, while maintaining selective 5-HT2A and 5-HT2C receptor antagonism.
Data Source
AI summary
Provided are a compound having 5-HT2A receptor antagonism and/or inverse agonism and 5-HT2C receptor antagonism and/or inverse agonism and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising them. A compound represented by Formula (I): wherein R1 is substituted or unsubstituted 6-membered aromatic heterocyclyl or the like, A1 is CR2 or the like, A2 is CR3 or the like, A3 is CR4 or the like, R2, R3, and R4 are each independently a hydrogen atom or the like, R5 is substituted or unsubstituted aromatic heterocyclyl or the like, R15 and R16 are each independently a hydrogen atom or the like, and R17 and R18 are each independently a hydrogen atom or the like, or a pharmaceutically acceptable salt thereof.