mGluR5 Positive Allosteric Modulators for Selective CNS Penetration
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Solution Overview
Problem
Developing selective mGluR5 agonists with acceptable CNS penetration and in vivo activity is challenging due to the high conservation of the glutamate binding site among mGluR family members, making it difficult to treat neurological and psychiatric disorders associated with NMDA receptor hypofunction.
Innovation Solution
Designing positive allosteric modulators of mGluR5 that bind to an allosteric site, modulating receptor activation without interfering with natural glutamate signaling, thereby potentiating NMDA receptor signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If agonists bind to the orthosteric glutamate binding site of mGluR5, then receptor activation is achieved, but selectivity among mGluR family members is lost due to high conservation of the binding site
Solution Approach 1:
The patent employs allosteric modulators as intermediary compounds that bind to a distinct site on the mGluR5 receptor rather than the orthosteric glutamate binding site. This intermediary binding approach allows modulation of receptor activity while avoiding direct competition at the conserved orthosteric site, thereby achieving both receptor activation and selectivity among mGluR family members
Solution Approach 2:
The invention targets a specific local region (allosteric site) on the mGluR5 receptor that differs from the highly conserved orthosteric binding site. By focusing on this distinct local quality of the receptor structure, the patent achieves selective modulation of mGluR5 without cross-reactivity with other mGluR subtypes
2Reliability
If agonists permanently activate the mGluR5 receptor, then strong therapeutic effect is achieved, but natural glutamate signaling is interfered with
Solution Approach 1:
Instead of using agonists that directly and permanently activate the receptor, the patent inverts the approach by using positive allosteric modulators that enhance the receptor's response to endogenous glutamate. This inversion allows the natural glutamate signaling to remain intact while amplifying its therapeutic effect through allosteric enhancement
3Productivity
If compounds are designed to penetrate the CNS, then in vivo activity is improved, but selectivity and specificity are reduced
Solution Approach 1:
The patent uses allosteric modulators as intermediary compounds that can penetrate the CNS blood-brain barrier while maintaining selectivity for mGluR5. The unique allosteric binding site provides a specific target that allows CNS penetration without sacrificing selectivity, as the allosteric site structure is sufficiently distinct from other mGluR subtypes
Data Source
AI summary
This invention relates to compounds of formula Itheir use as positive allosteric modulators of mGlu5 receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of neurological and psychiatric disorders associated with glutamate dysfunction such as schizophrenia or cognitive decline such as dementia or cognitive impairment. A, B, X, R1, R2, R3 have meanings given in the description.