Peripheral GABA-A Modulators for IBS Without CNS Side Effects

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Solution Overview

Problem

Current treatments for irritable bowel syndrome (IBS) are limited, with existing pharmacological approaches focusing on serotonin modulation leading to modest effectiveness and significant adverse effects, and GABA-A receptor modulators designed for central nervous system disorders causing CNS side effects.

Innovation Solution

Development of peripherally restricted GABA-A receptor positive allosteric modulators that selectively target the peripheral nervous system without crossing the blood-brain barrier, modulating GABA-A receptors to treat IBS and other peripheral disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If GABA-A receptor modulators are used to treat IBS, then therapeutic effect on gut motility and visceral pain is improved, but CNS side effects worsen

Engineering Contradiction:

Improvetherapeutic effectVSAvoidCNS side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the GABA-A receptor modulation effect by designing compounds that selectively target peripheral GABA-A receptors in the enteric nervous system while excluding central GABA-A receptors in the brain. This spatial segmentation allows therapeutic effects on gut motility and visceral pain without CNS side effects such as sedation and cognitive impairment.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies local quality by creating compounds with specific molecular properties (peripheral restriction) that enable selective action at peripheral GABA-A receptors in the gastrointestinal tract. The compounds possess chemical characteristics that allow them to cross the gut barrier but not the blood-brain barrier, providing localized therapeutic action with minimal systemic effects.

Inventive Principle:

Principle #3Local quality

2Reliability

If serotonin modulation is used to treat IBS, then gut motility is improved, but adverse effects worsen

Engineering Contradiction:

Improvegut motility treatmentVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent inverts the conventional approach by switching from serotonin modulation to GABA-A receptor modulation. Instead of targeting serotonin receptors which have been associated with adverse effects, the patent targets GABA-A receptors in the enteric nervous system, which provide similar therapeutic benefits for gut motility without the same adverse effect profile.

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If brain penetrating GABA-A modulators are used, then anxiety relief is improved, but sedation and addiction risk worsen

Engineering Contradiction:

Improveanxiety reliefVSAvoidsedation and addiction risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts the anxiolytic therapeutic effect from the harmful CNS side effects by designing peripherally restricted GABA-A modulators. The compounds are engineered to exclude penetration into the central nervous system through the blood-brain barrier, thereby taking out the beneficial peripheral effects on gut function while leaving behind the harmful CNS effects of sedation and addiction.

Inventive Principle:

Principle #2Taking out (Extraction)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Effective treatment of IBS and other peripheral disorders with reduced CNS side effects, including visceral pain, gut motility, and anxiety, by positively modulating GABA-A receptors in the enteric nervous system.

Implementation Method 1

positive allosteric modulators of one or more GABA-A receptors

Methodology Applied

Scientific EffectAllosteric modulation:

Implementation Method 2

Activation of neuronal GABA receptors results in hyperpolarization and stabilization of neuronal excitability

Methodology Applied

Scientific EffectGABA-A receptor activation:

Implementation Method 3

which do not substantially pass through the blood-brain barrier

Methodology Applied

Scientific EffectBlood-brain barrier restriction:

Data Source

PatentUS20260042763A1Peripherally restricted GABA positive allosteric modulators for the treatment of irritable bowel syndrome and other ailments of the peripheral nervous system

Publication Date: 2026.02.12 JOHNS HOPKINS UNIVERSITY

AI summary

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof, or an N-oxide thereof), which are positive allosteric modulators of one or more GABA-A receptors, e.g., which are peripherally restricted, positive allosteric modulators of one or more GABA-A receptors: e.g., which are positive allosteric modulators of one or more GABA-A receptors and which selectively target the peripheral nervous system and organs of the body, and which do not substantially pass through the blood-brain barrier. Said compounds are useful e.g., for the treatment of systemic diseases of the body. e.g., diseases in which modulation of one or more peripherally restricted GABA-A receptors is beneficial (e.g., diseases or disorders which are mediated by GABA-A neuronal activity. This disclosure also features pharmaceutical compositions containing the chemical entities described herein as well as methods of using same for the treatment of systemic diseases of the body.