RESUMO
The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual stereoisomers. The S isomer (4a) was found to be 12 times more potent than the R isomer (4b). Compound 4a demonstrated in vivo pharmacological activity in neuroprotection and anticonvulsant assays.
Assuntos
Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacologia , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Ataque Isquêmico Transitório/tratamento farmacológico , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/tratamento farmacológico , EstereoisomerismoRESUMO
The synthesis, biological activity, and single crystal X-ray structure of NPS 1392, (R)-(-)-3,3-bis(3-fluorophenyl)-2-methylpropan-1-amine (3a), a potent, stereoselective antagonist of the NMDA receptor, are described. The NMDA receptor selectively bound the levo isomer (3a) over its enantiomer (3b), which prompted a rigorous absolute configuration assignment. NPS 1392 has the R configuration based on the single-crystal X-ray diffraction analysis of the hydroiodide salt of NPS 1392. This compound is a potential neuroprotective agent for use in the treatment of ischemic stroke.
