title: Synthesis, resolution, and SAR of (+/-)-2-amino-N-methyl-alpha-(3-methyl-2-thienyl)benzeneethanamine++ + and related analogs as noncompetitive NMDA antagonists with neuroprotective properties.
abstract: The preparation and structure-activity relationships of a series of 2-amino-alpha-thienylbenzeneethanamines 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 noncompetitive NMDA antagonists with neuroprotective properties. Optical resolution of 3a and X-ray crystallography of (+)3a were performed. The racemate and enantiomers were evaluated for neuroprotective properties in models of ischemia-induced hippocampal damage (gerbil) and cerebral focal ischemia (rat). Pretreatment with 3a, (+)3a, or (-)3a significantly reduced ischemia-induced CA1 hippocampal damage. Posttreatment with 3a afforded a lower degree of neuroprotection. A highly significant reduction in infarct volume was observed with 3a in the cerebral focal ischemia model, with only weak positive effects being displayed by (+)3a. Dose-limiting side effects were associated with all three compounds in this model. In summary, the results demonstrate the utility of noncompetitive NMDA antagonists as neuroprotective agents for ischemia-induced neurodegeneration.
authors.affiliation: Hoechst-Roussel Pharmaceuticals Inc., Strategic Business Unit Neuroscience, Somerville, New Jersey 08876.
authors.forename: L L
authors.initials: LL
authors.lastname: Martin
authors.forename: G E
authors.initials: GE
authors.lastname: Lee
authors.forename: T B
authors.initials: TB
authors.lastname: Lee
authors.forename: D K
authors.initials: DK
authors.lastname: Rush
authors.forename: C A
authors.initials: CA
authors.lastname: Wilmot
authors.forename: E
authors.initials: E
authors.lastname: Paulus
authors.forename: U
authors.initials: U
authors.lastname: Elben
authors.forename: J J
authors.initials: JJ
authors.lastname: Grome
authors.forename: E
authors.initials: E
authors.lastname: Porsche-Wiebking
authors.forename: K A
authors.initials: KA
authors.lastname: Rudolphi
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000627:therapeutic use; D001667:Binding, Competitive; D002545:Brain Ischemia / Q000517:prevention & control; D002544:Cerebral Infarction / Q000517:prevention & control; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005849:Gerbillinae; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects; D007536:Isomerism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000814:Aniline Compounds; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; D013876:Thiophenes; D016202:N-Methylaspartate