28 Feb mGlu2 receptor Agonist ADX71149 Plus Levetiracetam May Reduce Seizures With Fewer Side Effects
MedicalResearch.com Interview with:
Robert Lutjens, PhD
Head of Discovery at Addex Therapeutics
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Metabotropic glutamate receptors represent an attractive therapeutic target for various neurologic conditions. In particular, the metabotropic glutamate receptor subtype 2 (mGlu2) can affect excitatory synaptic transmission by decreasing glutamate release. As excess gluatamate is observed in epilepsy, targeting mGlu2 could lead to new avenues of therapy. Positive allosteric modulators (PAMs) of mGlu2 could be valuable candidate drugs as they do not directly activate receptors. Therefore, they may avoid tachyphylaxis and side effects emerging from direct receptor agonism.
The publication summarizes the effects obtained when the mGlu2 receptor is activated using an agonist or PAM, such as ADX71149, in the 6Hz psychomotor seizure test, considered to be the most relevant model of pharmacoresistant limbic seizures. The data show that while seizures are reduced when mGlu2-acting compounds are administered alone, their combination with the antiseizure drug levetiracetam (LEV) result in a potent reduction of doses required to produce full efficacy, which is important because higher doses of LEV are associated with dose-limiting side effects, such as aggression, nervousness/anxiety, somnolence and fatigue. In this study, a fixed dose of ADX71149 was seen to increase the potency of LEV, leading to an approximate 35-fold increase in its potency. Conversely, using a fixed dose of LEV with varying doses of ADX71149 resulted in an approximate 14-fold increase in ADX71149 potency.
MedicalResearch.com: What should readers take away from your report?
Response: These studies suggest a potential positive pharmacodynamic effect of mGlu2-acting compounds in combination with LEV. If this effect is translated in a clinical setting, we believe it could support a rational polypharmacy concept in treatment of epilepsy patients.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: The results of this study could be used to inform the design and execution of future clinical trials. Addex is exploring with Janssen how best to move ADX71149 into a Phase 2a proof of concept study.
MedicalResearch.com: Is there anything else you would like to add?
Response: Allosteric modulators are an emerging class of orally available small molecule therapeutic agents that may offer a competitive advantage over classical drugs. This potential results from their ability to offer greater selectivity and better modulatory control at disease mediating receptors. Most marketed drugs bind receptors where the body’s own natural molecular activators (i.e. endogenous ligands) bind, specifically to a key part of each receptor’s anatomy called the “active site”. In short, most drugs must out-compete endogenous ligands in order to bind to the active site. By contrast, allosteric modulators are non-competitive because they bind receptors at a different site and modify receptor function even if the endogenous ligand also is binding. Because of this, allosteric modulators are not limited to simply turning a receptor on or off, the way most drugs are. Instead, they act more like a dimmer switch, offering control over the intensity of activation or deactivation, while allowing the body to retain its natural control over initiating receptor activation.
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Efficacy of mGlu2 -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures.
Metcalf CS1,2, Klein BD1,2, Smith MD2, Pruess T2, Ceusters M3, Lavreysen H3, Pype S4, Van Osselaer N3,5, Twyman R6, White HS2,7.
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