Triazole Allosteric Modulators for Nicotinic Receptor Desensitization

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Solution Overview

Problem

Current nicotinic receptor agonists for treating conditions associated with reduced nicotinic transmission face challenges such as desensitization and long-term inactivation, limiting their efficacy and duration of action.

Innovation Solution

Development of substituted 1-alkyl-3-aniline-5-aryl triazole derivatives as positive allosteric modulators that enhance the efficacy of nicotinic acetylcholine receptor agonists without causing long-term inactivation, thereby modulating α7 nicotinic receptors for therapeutic benefits.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If nicotinic receptor agonists are used to treat conditions with reduced nicotinic transmission, then receptor activation and therapeutic effect are improved, but desensitization and long-term inactivation occur reducing efficacy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidduration of receptor activation

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

Instead of using agonists that directly activate the receptor (which cause desensitization), the invention uses positive allosteric modulators that enhance the effect of endogenous agonists like acetylcholine. This inverse approach—modulating rather than directly activating—avoids desensitization while maintaining therapeutic efficacy through enhanced natural signaling

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent introduces positive allosteric modulators as intermediary substances that bind to a site distinct from the orthosteric agonist binding site. These modulators indirectly enhance receptor activation by stabilizing active conformations and increasing agonist affinity, rather than directly activating the receptor themselves, thus avoiding the desensitization pathway

Inventive Principle:

Principle #24Intermediary (Mediator)

2Duration of action of moving object

If prolonged activation of nicotinic receptors is achieved, then therapeutic benefits are enhanced, but long-lasting inactivation and desensitization occur

Engineering Contradiction:

Improveduration of receptor modulationVSAvoidreceptor responsiveness

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

By using positive allosteric modulators that enhance endogenous acetylcholine signaling, the system achieves periodic activation patterns that mirror natural cholinergic transmission. This allows sustained therapeutic effect through repeated natural signaling cycles without causing the continuous activation that leads to desensitization

Inventive Principle:

Principle #19Periodic action

Solution Approach 2:

The positive allosteric modulators work by enhancing the body's own acetylcholine rather than providing external continuous stimulation. This self-service mechanism allows the endogenous neurotransmitter system to naturally regulate activation patterns, preventing the receptor exhaustion that occurs with prolonged exogenous agonist administration

Inventive Principle:

Principle #25Self-service

Data Source

PatentEP2212309B1Trisubstituted 1,2,4-triazoles

Publication Date: 2013.06.19 JANSSEN PHARMA NV

AI summary

The present invention relates to substituted 1-(alkyl)-3-aniline-5-aryl triazole derivatives and analogues or pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, according to Formula (I). The invention particularly relates to potent positive allosteric modulators of nicotinic acetylcholine receptors which have the capability of increasing the efficacyofnicotinic receptor agonists.