Abstract
Although current antipsychotics, most of which are dopamine-based therapies, have been used to manage some of the symptoms of schizophrenia, a significant unmet need remains, requiring new treatment options. Accumulating evidence suggest that aberrant glutamatergic activity, including hyperactive cortical pyramidal neurons, contribute to the pathophysiology of schizophrenia, and that stimulation of group II metabotropic glutamate (mGlu2/3) receptor, which regulates heightened glutamate release, normalize hyperactivity of glutamatergic transmission. Therefore, mGlu2/3 receptor agonist may offer a novel mechanism to treat schizophrenia. However, clinical trials with Pomaglumetad, an mGlu2/3 receptor agonist developed by Eli Lilly, have not necessarily proven this hypothesis, presumably due to lack of clear proof-of-mechanisms at doses used in the trials. Taisho synthesized TS-134, a prodrug of an mGlu2/3 receptor agonist MGS0008. TS-134 was tested in a ketamine challenge pharmacological magnetic resonance imaging model in healthy volunteers, which may mimic hyper-glutamatergic states of schizophrenia.
In this symposium, I will introduce preclinical and phase I results of TS-134. Moreover, the approach to demonstrate a proof-of-mechanism in humans based on hyper-glutamatergic hypothesis of schizophrenia will be discussed.
