Alpha5 GABAA Receptor Modulators for Fast-Acting Antidepressants

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Solution Overview

Problem

Current treatments for depression and suicidality, such as SSRIs, require prolonged periods for therapeutic improvement and often have significant side effects, and there is a need for fast-acting antidepressants with fewer adverse effects.

Innovation Solution

Administration of negative allosteric modulators of the GABAA receptor, specifically targeting the alpha5 subunit, which can produce rapid antidepressant action by modulating GABAA receptor function, either alone or in combination with other antidepressant drugs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If SSRIs are used to treat depression, then antidepressant effect is achieved, but treatment duration is prolonged (weeks to months)

Engineering Contradiction:

Improveantidepressant effectVSAvoidtreatment duration

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent changes the pharmacological parameter from serotonin reuptake inhibition (SSRIs) to GABAA receptor modulation, specifically targeting alpha5 subunit-containing receptors. This parameter change enables rapid antidepressant effects within hours to days, resolving the contradiction between achieving reliable antidepressant effect and reducing treatment duration.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If SSRIs are used to treat depression, then antidepressant effect is achieved, but side effects are significant

Engineering Contradiction:

Improveantidepressant effectVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by selectively modulating GABAA receptors containing the alpha5 subunit, which are specifically distributed in certain brain regions. This selective targeting provides antidepressant effects with a different side effect profile compared to non-selective SSRIs, addressing the contradiction between effective treatment and minimizing harmful effects.

Inventive Principle:

Principle #3Local quality

3Speed

If ketamine is used as fast-acting antidepressant, then rapid antidepressant effect is achieved, but psychotomimetic side effects occur

Engineering Contradiction:

Improveonset of actionVSAvoidpsychotomimetic effects

Core Design Contradiction:

SpeedVSObject-generated harmful factors

Solution Approach 1:

The patent changes the mechanism parameter from NMDA receptor antagonism (ketamine) to GABAA receptor modulation. This parameter change maintains the rapid onset of action (hours to days) while producing a different pharmacological profile that avoids the psychotomimetic side effects associated with ketamine.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

By selectively targeting alpha5 subunit-containing GABAA receptors rather than using non-selective NMDA antagonism, the patent achieves rapid antidepressant effects with improved selectivity, resolving the contradiction between fast action and minimizing harmful psychotomimetic effects.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS11083732B2Use of negative modulators of GABA receptors containing alpha5 subunits as fast acting antidepressants

Publication Date: 2021.08.10 UNIV OF MARYLAND

AI summary

Embodiments of the disclosure include methods and compositions related to treatment of one or more medical conditions with one or more negative modulators of GABAA receptors. In specific embodiments, depression and/or suicidability is treated or ameliorated or prevented with one or more negative modulators of GABAA receptors, such as a partial inverse agonist of a GABAA receptor comprising an alpha5 subunit.