mGluR2 NAM

The metabotropic receptor mGluR2 belongs to the class C GPCR family (group II mGluRs). This receptor shows a broad distribution throughout the cortex as well as high expression in the hippocampus and perforant path.

Importantly, activation of mGluR2 leads to inhibition of glutamate release in the synapse. In this respect, Addex believes that inhibition of mGluR2 with a selective negative allosteric modulator (NAM) may be of therapeutic use to treat medical conditions which may be linked to low glutamate levels in the brain. Alzheimer’s disease and depression are prime examples of such conditions.

Disabilities such as Alzheimer’s or depression represent a large and growing market with considerable unmet medical needs. For example, none of the currently marketed drugs for Alzheimer’s disease offers patients sustained life-changing benefits. Preclinical data suggest that mGluR2 inhibition may result in therapeutic benefits in the treatment of cognitive disorders such as Alzheimer's as well as depression. In addition, peer-reviewed research suggests that an mGluR2 NAM not only may slow the progression of Alzheimer’s* (an effect not yet described with any marketed drug) but also that such a drug may exert a synergistic effect on cognition when combined with donepezil**.

Addex is currently optimizing multiple chemical series of mGluR2 NAMs offering advanced compounds at the late stage of lead optimization. Recently, one such mGluR2 NAM  was tested in the beta amyloid-induced memory impairment model in rodents which mimics aspects of pathophysiology and progressive memory impairment observed in Alzheimer’s disease. In this study, an advanced mGluR2 NAM used as a tool compound dose-dependently reversed working memory impairment in the novel object recognition test (NOR) without affecting locomotor activity in the animals. Donepezil, a marketed drug currently used to treat symptoms of Alzheimer’s disease, was used as the positive control and we are excited to report that the magnitude of the effect induced by the mGluR2 NAM was similar to that of donepezil in this experiment.

Although other drugs targeting mGluR2 are in development none are known to be as exquisitely selective for mGluR2 over other mGlu receptors (1-8) as the Addex molecules. As a result, Addex is developing the most advanced subtype selective mGluR2 NAM, an differentiating factor that may confer significant advantages in terms of efficacy and safety in later testing.