Redefining Brain Health With Allosteric Modulation
Understanding Allosteric Modulation
Traditional drugs bind at the receptor’s active (orthosteric) site, directly competing with the body’s natural signaling molecules. This often produces an all-or-nothing effect and can trigger unwanted side effects.
In contrast, allosteric modulators bind to distinct receptor sites – the allosteric sites. This allows them to fine-tune receptor activity rather than simply turning signaling on or off. Think of it as a dimmer switch instead of a light switch.
PAMs and NAMs: Two Modes of Control
Allosteric modulators can either enhance or dampen signaling, depending on therapeutic need:
Positive Allosteric Modulators (PAMs): Boost the receptor’s natural response, amplifying signaling strength.
Negative Allosteric Modulators (NAMs): Reduce excessive receptor activity without shutting it down completely.
The Allosteric Advantage in Therapeutics
Allosteric modulators represent a new generation of small-molecule medicines with potential benefits compared to traditional agonists and antagonists:
1.
Precise Modulation of Neurotransmission
Fine-tune receptor responses more like a dimmer switch than an on/off button, likely reducing the risk of overactivation or disruption in unintended brain circuits
2.
Greater Specificity and Selectivity
By binding outside of the orthosteric site, allosteric modulators may achieve stronger target specificity, lowering the likelihood of off-target interactions and side effects
3.
Improved Safety and Tolerability
Allosteric modulators have the potential to work in concert with the body’s natural ligands, supporting physiological balance while avoiding the overstimulation or suppression often associated with traditional drugs
Our Pipeline: Precision by Design
We are advancing a focused pipeline of first- and best-in-class allosteric modulators for neuropsychiatric disorders:
- NTX-253 and NTX-529 (best-in-class M4 PAMs): Unlocking the therapeutic potential of muscarinic modulation in schizophrenia and related disorders.
- NTX-819 (first-in-class mGlu7 NAM): Targeting glutamatergic circuits for mood and anxiety disorders.
Discovery Engine
At Neurosterix, our discovery engine powers the creation of first- and best-in-class therapies for neuropsychiatric care. By combining innovative medicinal chemistry, deep receptor pharmacology, and advanced screening technologies, we generate novel allosteric modulators that precisely modulate brain circuits and rapidly translate into pipeline candidates addressing urgent unmet needs.
What makes our engine powerful:
Presentations & Publications
Key presentations and publications that demonstrate the foundation and progress of our research:
Effect of the Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulator Dipraglurant on Motor and Non-Motor Symptoms of Parkinson’s Disease
Cells
Pharmacological and Pharmacokinetic Properties of JNJ-40411813, a Positive Allosteric Modulator of the mGlu2 Receptor
Pharmacology Research & Perspectives
Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders
The Journal of Pharmacology and Experimental Therapeutics
ADX71743, a Potent and Selective Negative Allosteric Modulator of Metabotropic Glutamate Receptor 7: In Vitro and In Vivo Characterization
The Journal of Pharmacology and Experimental Therapeutics
A Potent and Selective mGluR4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson’s Disease
The Journal of Pharmacology and Experimental Therapeutics
Characterization of an mGluR2/3 Negative Allosteric Modulator in Rodent Models of Depression and Comparison with the Reference mGluR2/3 Orthosteric Antagonist LY341495
Journal of Neurogenetics
mGluR5 Negative Allosteric Modulators Overview: A Medicinal Chemistry Approach Towards a Series of Novel Therapeutic Agents
Current Topics in Medicinal Chemistry
Editorials
Glutamate Receptor Modulators as Emergent Therapeutic Agents in the Treatment of Parkinson’s Disease
Chapter 10 in Emerging Drugs and Targets for Parkinson’s Disease, RSC drug discovery series vol 34
New Technologies Enabling the Industrialization of Allosteric Modulator Discovery
Drug Discovery Today: Technologies
Recent Advances in the Drug Discovery of Metabotropic Glutamate Receptor 4 (mGluR4) Activators for the Treatment of CNS and Non-CNS Disorders
Expert Opinion on Drug Discovery
mGluR2 Activators and mGluR5 Blockers Advancing in the Clinic for Major CNS Disorders
Annual Reports in Medicinal Chemistry