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.

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

“…1), act as noncompetitive NMDA antagonists, and prevent clonic seizures in mice induced by (Ϯ)ϪN-methylaspartic acid (ED 50 ϭ 6.4 mg/kg, i.p., when R 1 ϭ C 2 H 5 , R 2 ϭ H, X ϭ H, and Y ϭ 3-CH 3 ). 60 The amino acid 7 ( Fig. 1), bearing the acidic tetrazole ring substituent, also a potent and selective NMDA antagonist, shows ability to block NMDA-induced convulsions in neonatal rats (the minimum effective dose, 20 mg/kg, i.p.)…”

Synthesis and Structure−Activity Relationships of N-Propyl-N-(4-pyridinyl)-1H-indol-1-amine (Besipirdine) and Related Analogs as Potential Therapeutic Agents for Alzheimer's Disease

“…Biological Methods. Procedural details for the in vivo prevention of tetrabenazine-induced (TBZ) ptosis 41,42 and reversal of scopolamine dementia dark avoidance (SDDA), , and in vitro inhibition of synaptosomal biogenic amine (norepinephrine, serotonin, dopamine) uptake 6,44 and inhibition of [ 3 H]quinuclidinyl benzilate (QNB), 24, 26,44 [ 3 H]- N -methylscopolamine, [ 3 H]SCH23390, [ 3 H]spiroperidol, [ 3 H]WB4101, , [ 3 H]clonidine, [ 3 H]yohimbine, [ 3 H]idazoxan, , [ 3 H]-(±)-[3-(2-carboxypiperazin-4-yl)propyl]phosphonate (CPP), [ 3 H]- N -[1-(2-thienyl)cyclohexyl]piperidine (TCP), [ 3 H]nitrendipine, [ 3 H]-8-hydroxy-2-(di- n -propylamino)tetralin (DPAT), [ 3 H]dihydromorphine (DHM), [ 3 H]bremazocine, [ 3 H]pirenzepine, [ 3 H]oxotremorine-M 55 and [ 3 H]- N -methylcarbamylcholine 56 binding were previously reported. In vitro inhibition of acetylcholinesterase was determined by the method of Ellman …”

“…[ 3 H]-(()-[3-(2-carboxypiperazin-4-yl)propyl]phosphonate (CPP), 49 [ 3 H]-N-[1-(2-thienyl)cyclohexyl]piperidine (TCP),49 [ 3 H]nitrendipine, 50 Potential Therapeutic Agents for Alzheimer's Disease Journal of Medicinal Chemistry, 1996, Vol. 39, No.…”