GABAA Receptor Modulators with Heteroaromatic Rings for Selective Binding

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Solution Overview

Problem

Current compounds for modulating GABAA receptors do not function as CNS depressants and lack novel structures for specific inhibition or modulation of the human α1β3γ2 receptor, limiting their anxiolytic, sedative, and hypnotic effects.

Innovation Solution

Development of GABAA receptor-binding compounds of Formulas IA and IB, which include specific heteroaromatic rings and substitution patterns, demonstrated to act as positive allosteric modulators or inhibitors of the human α1β3γ2 GABAA receptor, capable of modulating physiological and pathological processes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If prior art GABAA receptor modulators are used, then GABAA receptor modulation is achieved, but CNS depressant effects and specific inhibition of human α1β3γ2 receptor are not obtained

Engineering Contradiction:

Improvespecific inhibition of human α1β3γ2 receptorVSAvoidCNS depressant effects

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by introducing specific substitution patterns at defined positions on the heteroaromatic ring (R1-R4 substituents) to achieve selective binding to the human α1β3γ2 GABAA receptor subtype. This localized structural modification enables specific receptor subtype inhibition while maintaining overall GABAA modulation capability.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying the heteroaromatic ring structure and substituent groups (R1-R4) to optimize binding affinity and selectivity for the human α1β3γ2 receptor. These structural parameter modifications transform the compound profile from general GABAA modulation to specific CNS depressant activity with desired anxiolytic, sedative, and hypnotic effects.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If general GABAA receptor modulators are used, then broad GABAA activity is achieved, but novel structures for specific human α1β3γ2 receptor modulation are lacking

Engineering Contradiction:

Improvebroad GABAA activityVSAvoidnovel structure specificity

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies segmentation by dividing the GABAA receptor modulator class into distinct structural categories based on the heteroaromatic ring type and substitution patterns. This segmentation creates novel compound series (Formulas IA, IB, and II) with defined structural features that confer specific binding characteristics to the human α1β3γ2 receptor while maintaining broad GABAA activity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs composite materials by combining the heteroaromatic core structure with specific substituent groups (R1-R4) to create composite molecular structures. These composite compounds integrate multiple functional elements that work synergistically to achieve both broad GABAA receptor activity and specific binding to the human α1β3γ2 subtype.

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS11911364B2Positive allosteric modulators of GABA<sub>A </sub>receptor

Publication Date: 2024.02.27 PEPTICOM LTD

AI summary

The present invention provides new GABAA receptor-binding compounds that modify the activation of GABAA, their use in the preparation of a neuroactive pharmaceutical composition, improving sperm motility and labeling of biomolecules.