SYNTHESIS, RESOLUTION, AND SAR OF (+ METHYL-ALPHA-(3-METHYL-2-THIENYL)BENZENEETHANAMINE AND RELATED ANALOGS AS NONCOMPETITIVE NMDA ANTAGONISTS WITH NEUROPROTECTIVE PROPERTIES/

The preparation and structure-activity relationships of a series of 2- amino-alpha-thienylbenze-neethanamines are described. From this work, (+/-)-2-amino-N-methyl-alpha-(3-methyl-2-thienyl)- benzeneethanamine ( 3a) and the homologous N-ethyl analog 3b emerged as novel noncompetiti ve NMDA antagonists with neuroprotective properties. Optical resolutio n of 3a and X-ray crystallography of( +)3a were performed. The racemat e and enantiomers were evaluated for neuroprotective properties in mod els of ischemia-induced hippocampal damage (gerbil) and cerebral focal ischemia (rat). Pretreatment with 3a, (+)3a, or (-)3a significantly r educed ischemia-induced CA1 hippocampal damage. Posttreatment with 3a afforded a lower degree of neuroprotection. A highly significant reduc tion in infarct volume was observed with 3a in the cerebral focal isch emia model, with only weak positive effects being displayed by (+)3a. Dose-Limiting side effects were associated with all three compounds bn this model. In summary, the results demonstrate the utility of noncom petitive NMDA antagonists as neuroprotective agents for ischemia-induc ed neurodegeneration.