SEARCHING FOR THE ‘MAGIC PILLS’ FOR UNMET MEDICAL NEEDS IN SCHIZOPHRENIA AND OTHER NEUROPSYCHIATRIC DISORDERS: LEARNING FROM A NOVEL DAO INHIBITOR

Abstract Excitatory neurotransmission mediated by N-methyl-D-aspartate receptor (NMDAR, a glutamate receptor) is primitive to and widely spread in mammalian central nervous system. It has been implicated in many fundamental functions and complex mental functions, including neuronal plasticity, learning, memory, and schizophrenia. Schizophrenia, a severe mental illness, affects 1% of population worldwide, including Taiwan. Common symptoms associated with schizophrenia include positive, negative, and cognitive symptoms. While existing agents treat positive symptoms of schizophrenia relatively well, negative and cognitive symptoms of schizophrenia have become an unmet medical need for antipsychotics development. In recent decades, increasing evidence from genetic, clinical, and pharmacological studies supports the NMDAR hypofunction hypothesis of schizophrenia. Blockade of the NMDAR can precipitate schizophrenic-like symptoms in both normal humans and animal models. Notably, several NMDA-enhancing agents, especially through glycine modulatory site (GMS) of NMDAR, resulted in a significant reduction of schizophrenia-related symptoms in patients. Particularly, D-amino acid oxidase (DAO) is now of great interest for the treatment of schizophrenia and several psychiatric disorders because its major substrate in the brain is D-serine, a co-agonist of the GMS on NMDAR. Accumulating data also provide clear evidence of increased cerebellar DAO (mRNA and enzyme activity) in schizophrenia. DAO inhibitor is one of the most attractive therapeutic targets for improving cognition and reducing negative symptoms in schizophrenia. Our inter-institutional research team has developed RS-D7 (a new chemical entity and a novel DAO inhibitor) for the treatment of negative and cognitive symptoms of schizophrenia for several years and obtained several awards. Given that NMDAR-mediated signaling pathway has been implicated in cognitive functions and that DAO inhibitors are potential therapeutic targets for enhancing activation of NMDARs, it is of great interest to investigate the effects of RS-D7 on the regulation of schizophrenia-related deficits and the underlying neural mechanisms in pharmacological (i.e., MK-801-induced) and genetic (i.e., serine racemase mutant) NMDAR hypofunction mouse models of schizophrenia. A series of cell-based assays and mouse studies was conducted and indicated efficacy, therapeutic effects, and underlying mechanism of RS-D7. Taking advantage of RS-D7 can be converted through a market drug RS-D7pro, our team further demonstrated RS-D7’ s significant therapeutic potentials in negative/cognition symptoms of schizophrenia and other neuropsychiatric disorders (e.g., multiple system atrophy) in our proof-of-concept clinical studies. Collectively, the therapeutic potentials of DAO inhibitors (especially RS-D7) on schizophrenia and other neuropsychiatric disorders are worth further investigation.