Design, Synthesis And Activity Screening Of NMDA Receptor Glycine Binding Site Agonists

Depression is a debilitating mental illness whose pathogenic mechanism is complex leading to severe consequences.And the patients continue to experience low remission rates,relapses and persistent functional impairment.The traditional depression therapies of antidepressant are slow in onset for patients to obtain a response.Neuroplasticity theories has emerged as a new class of antidepressant,which hold the view that the neurons in the brain compensate for injury and adjust their activity in response to new situations or changes in their environment.Glutamate is the major excitatory neurotransmitter in the brain,which is released from nerve cells,binds to receptors and is removed by reuptake transporters.NMDARs are part of the ionotropic glutamate receptor family,playing a critical role in regulation of neuroplasticity,learning and memory.At present,the mechanism of many researching new pattern of depression medicines is in view of NMDARs,possessing of rapid-onset and longer the effective time,such as ketamine,CERC-301,AV-101,GLYX-13 and NRX-1074.In this thesis,NRX-1074 was selected as a lead and chemically modified by changing.According to ring-expansion and exchanging acyl groups or amino substituents,the structures of twenty-four synthetic compounds were characterized by 1H-NHR,13C-NMR and Mass Spectrometry.The blank currents(Imax)were assayed after the calcium salt solution containing 100μM glutamate and 20μM glycine was introduced to oocytes and activated their NMDA receptors.Glycine in the calcium salt solutions was replaced by tested compounds with different concentrations and resulted currents(I)were determined for the calculation of Imax/I ratios that were used to establish dose-effect curves and calculate median effect concentrations of tested compounds.The results showed that LYJ-1,LYJ-13 and LYJ-19 were weak agonists of NMDA receptor.