SYNTHESIS, RESOLUTION, AND SAR OF (+ METHYL-ALPHA-(3-METHYL-2-THIENYL)BENZENEETHANAMINE AND RELATED ANALOGS AS NONCOMPETITIVE NMDA ANTAGONISTS WITH NEUROPROTECTIVE PROPERTIES/
Ll. Martin et al., SYNTHESIS, RESOLUTION, AND SAR OF (+ METHYL-ALPHA-(3-METHYL-2-THIENYL)BENZENEETHANAMINE AND RELATED ANALOGS AS NONCOMPETITIVE NMDA ANTAGONISTS WITH NEUROPROTECTIVE PROPERTIES/, Journal of medicinal chemistry, 37(19), 1994, pp. 3008-3015
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.