Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, announced that systemic treatment with its proprietary mGlu2 receptor negative allosteric modulator (NAM), ADX92639, protects vulnerable neurons against global ischemia in rats.

The neuroprotective effect of ADX92639 was studied in the 4-vessel occlusion (4VO) model of transient global ischemia in adult male rats. 4VO causes extensive degeneration of hippocampal CA1 pyramidal neurons, whereas neurons of the CA3 region are relatively spared. ADX92639 protected the CA1 neurons from ischemic neuronal death after oral administration of 30 mg/kg. The study builds on the evidence that induction of ischemia causes changes in the expression of mGlu2 receptors in the vulnerable CA1 region of the hippocampus. The data presented at the 2014 American Neuroscience Meeting, Washington D.C., was generated in collaboration with Marta Motolese, Federica Mastroiacovo, Milena Cannella, Giuseppe Battaglia and Ferdinando Nicoletti of IRCCS Neuromed, Italy.

"Neuromed scientists are world leading experts in mGlu receptor pharmacology and we are proud to have the opportunity to work with them" says Sonia Poli CSO at Addex. "These data together with data generated with our proprietary mGluR2 NAM's in the beta amyloid-induced memory impairment model support our continued efforts to bring these compounds into development."

The metabotropic receptor 2 (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 and mGluR2 NAM is one of the most promising experimental therapeutic strategies for the treatment of cognitive impairment in Alzheimer's disease. One of the Addex 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, the Addex mGluR2 NAM 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 the magnitude of the effect induced by the mGluR2 NAM was similar to that of donepezil in this experiment. Preclinical research from other groups suggest not only that mGluR2 NAM might slow the progression of Alzheimer's, an effect not seen with any marketed drug, but also that it may have a synergistic effect on cognition when combined with donepezil. Alzheimer's disease represents a large and growing market with unmet medical need. None of the currently marketed drugs for Alzheimer's disease offers patients sustained life-changing benefits. Addex is currently optimising multiple chemical series of mGluR2 NAMs offering advanced compounds at the late stage of lead optimization. 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 compounds. As a result, Addex is developing the most advanced subtype selective mGluR2 NAM, a differentiating factor that may confer significant advantages in terms of efficacy and safety in later testing.