Discovery and Pharmacological characterization of mGlu7 negative allosteric modulators for Post-Traumatic Stress Disorders – Seven4PTSD

Post-Traumatic Stress Disorder (PTSD) is a serious chronic and debilitating psychiatric disorder that can develop following exposure to a traumatic or stressful event. To date, there is no specific and efficient treatment for PTSD, and the current medications based on antidepressants are not affording benefit to patients, exhibit poor safety, and are associated with co-occuring devastating disorders. Therefore a breakthrough pharmacotherapy is urgently needed.
Neuroimaging studies highlighted abnormalities in the neural circuits in cerebral regions (i.e. PFC, hippocampus and amygdala), implicated in fear learning abnormalities, contextual memory deficits and sensitization, reported in PTSD patients. Microdialysis studies also showed that acute environmental stress rapidly and transiently induces a marked increase in the level of an extracellular neurotransmitter, called glutamate, in such brain areas. Therefore, a growing body of evidence suggests that glutamatergic neurotransmission is involved in the biological mechanisms underlying stress response and anxiety-related disorders.

In particular, the metabotropic glutamate receptor subtype-7 (mGlu7 receptor), which belongs to the Class C GPCR of the mGlu receptor family (8 subtypes), is uniquely distributed in the three aforementioned cerebral regions, and mGlu7 receptors have shown regulating fear and aversive memories associated to acute and chronic stress, such as in PTSD. Specific molecules dampening excessive glutamate release upon stressful event, allowed significant reduction in both anxiety, stress and fear measures in animal models. The mGlu7 receptor is in prime position to act as a key tuner of imbalance glutamate levels involved in such severe stress disorders, and represents an innovative mechanism of action for the treatment of stress-related anxiety, acute stress disorders (ASD), PTSD and other associated mood disorders.

Pragma Therapeutics has successfully identified highly active and selective blockers, acting at a specific (“ allosteric”) site of the mGlu7 receptor. Within these so called mGlu7 negative allosteric modulators (mGlu7 NAM), PGT117, represent an excellent starting point to further explore the structure-activity relationship along initial in vivo characterization. In addition, a second active molecule, PGT001, has been selected as a pharmacological tool to initiate radiolabelling and neuroimaging studies to probe mGlu7 target engagement in rodents. Additional proprietary molecules are under preparation for further in vitro characterization and metabolism studies in order to select the most promising series which will be fully optimized towards candidates during the course of this 2-year "Seven4PTSD" project.

Seven4PTSD is a public-private partnership, gathering 4 multidisciplinary and complementary teams across 4 different sites in France, all being experts in preparing, screening, evaluating and imaging novel ligands acting at a novel receptor for brain disorders.

The "Seven4PTSD" project will provide to the partners new specific, active, systemically available, brain penetrant molecules available for further in vitro and in vivo investigation, as well as a set of promising candidates for further non regulatory preclinical development at Pragma Therapeutics. Understanding mGlu7 biology and pharmacology, brain circuitry and imaging for future PTSD biomarkers investigation, will definitely help us to provide a new pharmacotherapeutic alternative to current and unsatisfying standards of care, for the benefit of patients.