Addex Therapeutics Publishes Breakthrough Data on mGlu7 Targeting for Anxiety and PTSD Treatment
核心洞察
Addex Therapeutics (搜索) published preclinical data in Molecular Psychiatry demonstrating that targeting mGlu7 (搜索) with negative allosteric modulators can disrupt fear memory reconsolidation in anxiety (搜索) and PTSD (搜索).
The selective mGlu7 (搜索) NAM compound ADX71743 (搜索) successfully interfered with fear memory reconsolidation in rat models, offering a time-limited therapeutic intervention approach.
Electrophysiological analyses showed the compound modulated glutamatergic transmission at key brain synapses, with similar effects observed in human brain tissue.
Addex Therapeutics (搜索) announced the publication of preclinical data in Molecular Psychiatry demonstrating that targeting metabotropic glutamate receptor 7 (搜索) (mGlu7 (搜索)) with negative allosteric modulators (NAM) could transform treatment approaches for anxiety (搜索) and fear-related disorders, including post-traumatic stress disorder (搜索) (PTSD (搜索)). The research, conducted by scientists from the Center for Psychiatric Neurosciences (搜索) (CNP, CHUV/UNIL) in Lausanne, Switzerland, provides compelling evidence for a novel therapeutic mechanism that targets fear memory reconsolidation.
Targeting Fear Memory Reconsolidation
The study evaluated ADX71743 (搜索), a highly selective mGlu7 (搜索) NAM, in established models of fear learning and memory. Results demonstrated that mGlu7 modulation can selectively interfere with the reconsolidation of fear memories, the process by which the brain re-stabilizes a fear memory after it is recalled. This process is increasingly recognized as a potential therapeutic intervention point in anxiety (搜索) and trauma-related conditions.
"Anxiety (搜索)- 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 (搜索), which can carry risks of tolerance, dependence and relapse after discontinuation."
Mechanistic Insights and Cross-Species Validation
Fear memories are encoded in the lateral amygdala, a central node in emotional processing. When recalled, these memories transiently enter a labile state during which they can be modified. The study showed that administration of ADX71743 (搜索), either directly into the lateral amygdala or systemically, disrupted fear memory reconsolidation in rats. This effect on reconsolidation was specific to the conditioned stimulus, required fear memory recall, occurred in a defined time window after recall, and significantly decreased reinstatement of fear.
Electrophysiological analyses provided mechanistic support for mGlu7 (搜索) target engagement. ADX71743 (搜索) modulated glutamatergic transmission at thalamus-to-amygdala synapses, which are critical for fear learning. Under baseline conditions, the compound increased spontaneous excitatory signaling, while under high-stimulation conditions it prevented long-term potentiation (LTP), a cellular process associated with memory formation.
Notably, similar synaptic effects were observed in human brain tissue, mirroring findings in rodent models. This cross-species consistency provides early translational validation and helps address a common risk factor in central nervous system drug development.
Clinical Implications and Future Development
Prof. Ron Stoop from the Center for Psychiatric Neurosciences (搜索) and paper author noted: "This research shows that fear memories can be weakened by targeting reconsolidation with a drug acting on mGlu7 (搜索). 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."
The research represents a departure from traditional anxiety (搜索) treatments that focus on symptom suppression. Instead of requiring continuous medication use like benzodiazepines (搜索), this approach targets the underlying fear memory mechanisms, potentially offering more durable therapeutic benefits with time-limited interventions.
About mGlu7 and Drug Development Pipeline
mGlu7 (搜索) is one of the most expressed receptors within the family of eight mGlu receptors and is thought to play a central role in multiple CNS functions, including emotional and stress reactivity, learning, memory and attention. Because of this multifactorial role, mGlu7 is considered a promising target for potential treatment of various disorders, including PTSD (搜索), obsessive compulsive disorder (搜索), anxiety (搜索), depression (搜索), drug abuse and schizophrenia (搜索).
Addex previously built one of industry's largest library of allosteric modulators targeting metabotropic glutamate receptors. As a result, several novel chemical series of mGlu7 (搜索) NAMs were identified and optimized. These compounds were included in the Neurosterix (搜索) spin-out transaction, positioning the research for future clinical development.