KCNQ Channel Agonists for Selective Neuronal Excitability Control

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Solution Overview

Problem

There is a need for safe, effective, and reliable KCNQ openers to manage neuronal excitability and electrical activity in various cell types, including cardiac myocytes, epithelial, and endothelial cells, as existing KCNQ openers like retigabine have shown unexpected side effects.

Innovation Solution

The method involves activating heteromeric KCNQ2/3, KCNQ3/5, or KCNQ4/5 voltage-gated potassium channels by contacting the cell membrane with specific agents that bind to KCNQ2, KCNQ3, KCNQ4, or KCNQ5 subunits, such as mallotoxin, isovaleric acid, retigabine, gabapentin, and their derivatives.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If retigabine is used to activate KCNQ channels for therapeutic effect, then neuronal excitability is reduced and epilepsy symptoms are treated, but unexpected side effects occur leading to market withdrawal

Engineering Contradiction:

Improvetherapeutic reliabilityVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the KCNQ channel activation function by identifying and targeting specific subunit combinations (KCNQ2/3, KCNQ3/5, KCNQ4/5 heteromers) with selective agonists. This segmentation allows for more precise therapeutic action on specific channel types involved in neuronal excitability while potentially avoiding side effects associated with non-selective KCNQ activation by retigabine.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies local quality by developing agonists with selective affinity for specific KCNQ subunit combinations rather than all KCNQ channels. This selective binding creates localized therapeutic effects on specific channel types in the nervous system while minimizing off-target effects on other KCNQ-expressing tissues such as cardiac myocytes and epithelial cells.

Inventive Principle:

Principle #3Local quality

2Reliability

If higher doses of KCNQ openers are used to achieve therapeutic effect, then channel activation is enhanced, but side effects increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the selectivity parameter of KCNQ channel activation by designing agonists with specific binding preferences for certain subunit combinations. This parameter change allows achieving therapeutic efficacy through selective high-affinity binding to target channels at lower concentrations, thereby reducing the need for high doses that cause side effects.

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If selective KCNQ subunit agonists are used to reduce side effects, then therapeutic safety is improved, but the complexity of identifying and developing specific agonists increases

Engineering Contradiction:

Improveside effectsVSAvoiddrug development complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent employs dynamics by using structure-activity relationship (SAR) analysis to systematically optimize agonist structures for selective binding to specific KCNQ subunit combinations. This dynamic optimization process allows for rational drug design that balances selectivity requirements with development feasibility, progressively refining compound specificity through iterative structural modifications.

Inventive Principle:

Principle #15Dynamics

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

This approach effectively activates KCNQ channels, reducing neuronal excitability and potentially ameliorating symptoms of epilepsy, anxiety, neuropathic pain, and other conditions, while minimizing side effects by using lower doses of KCNQ openers.

Implementation Method 1

contacting the cell membrane with a first agent that binds a KCNQ2 or KCNQ5 subunit

Methodology Applied

Scientific EffectLigand binding:

Implementation Method 2

contacting the cell membrane with a second agent that binds a KCNQ3 or KCNQ4 subunit

Methodology Applied

Scientific EffectLigand binding:

Implementation Method 3

activating heteromeric KCNQ2/3, KCNQ3/5, or KCNQ4/5 voltage-gated potassium channels

Methodology Applied

Scientific EffectIon channel conduction: Conduction (electrical)

Data Source

PatentUS12268683B2Compounds and methods for synergistic activation of M channels

Publication Date: 2025.04.08 RGT UNIV OF CALIFORNIA

AI summary

A method of activating heteromeric KCNQ2/3, KCNQ3/5, or KCNQ4/5 voltage-gated potassium channels in a cell membrane is described, as are compositions for use with same, as well as methods of reducing neuronal excitability and of ameliorating symptoms of epilepsy, anxiety, neuropathic pain, hypertension, cardiovascular disease, a neurodegenerative disorder, alcohol withdrawal, cancer, inflammation, or ophthalmic disease in a subject. These KCNQ2/3 (or KCNQ3/5 or KCNQ4/5) channels are heteromers that comprise KCNQ2 (or KCNQ5) subunits and KCNQ3 (or KCNQ4) subunits. In one embodiment, the method comprises: (a) contacting the cell membrane with a first agent that binds a KCNQ2 (or KCNQ5) subunit; and (b) contacting the cell membrane with a second agent that binds a KCNQ3 (or KCNQ4) subunit.