Targeting mGlu7 could lead to new anxiety and PTSD treatments

Addex Therapeutics, a clinical-stage biopharmaceutical company developing novel small molecule allosteric modulators for neurological disorders, has announced new research that could lead to new treatments for anxiety and fear-related conditions, such as post-traumatic stress disorder (PTSD). Their recently published data shows that targeting the metabotropic glutamate receptor 7 (mGlu7) with negative allosteric modulators (NAMs) may offer a powerful therapeutic approach.

Targeting fear memory reconsolidation

The study, conducted by scientists at the Center for Psychiatric Neurosciences (CNP, CHUV/UNIL) in Lausanne, Switzerland, investigated the effects of ADX71743, a highly selective mGlu7 NAM, in established animal models of fear learning and memory. Researchers found that modulating mGlu7 can selectively interfere with the reconsolidation of fear memories, a process where the brain re-stabilises a fear memory after it is recalled.

“Anxiety- and stress-related disorders remain among the most prevalent neuropsychiatric conditions globally, with many patients experiencing incomplete or transient responses to existing therapies,” said Tim Dyer, CEO of Addex. “This is because drugs used to treat anxiety disorders have mainly targeted symptoms and often require continuous use, such as benzodiazepines, which can carry risks of tolerance, dependence and relapse after discontinuation. This new research, targeting memory reconsolidation, provides a different therapeutic avenue to explore and continues to support our long-term belief that targeting mGlu7 with negative allosteric modulators is a differentiated mechanism to treat anxiety and fear-related disorders.”

Disrupting fear memories in the brain

Fear memories are encoded in the lateral amygdala, a central hub for emotional processing. When these memories are recalled, they temporarily enter a labile state where they can be modified. The study showed that administration of ADX71743, either directly into the lateral amygdala or systemically, disrupted fear memory reconsolidation in rats. This effect was specific to the conditioned stimulus, required memory recall, occurred within a defined time window after recall and significantly reduced the reinstatement of fear.

Mechanistic insights from electrophysiology

Electrophysiological analysis provided further support for mGlu7 engagement. ADX71743 was shown to modulate glutamatergic transmission at thalamus-to-amygdala synapses, crucial for fear learning. Under baseline conditions, the compound increased spontaneous excitatory signalling, while under high-stimulation conditions it prevented long-term potentiation, a key cellular process in memory formation. Similar synaptic effects were observed in human brain tissue, offering early translational validation and addressing a common risk factor in central nervous system drug development.

“This research shows that fear memories can be weakened by targeting reconsolidation with a drug acting on mGlu7. It offers a realistic path towards a time-limited pharmacological intervention, which combined with memory recall, could reduce pathological fear more durably than continuous symptom-suppressing medication,” said Professor Ron Stoop, a paper author from the Center for Psychiatric Neurosciences.

A strong foundation for drug discovery

Addex has previously built one of the industry’s largest libraries of allosteric modulators targeting metabotropic glutamate receptors. From this library, several novel chemical series of mGlu7 NAMs were identified and optimised, forming part of the Neurosterix spin-out transaction. These findings will be key in the future development of differentiated therapies for patients with anxiety and PTSD.