5-AMINOCOUMARANS - DUAL INHIBITORS OF LIPID-PEROXIDATION AND DOPAMINERELEASE WITH PROTECTIVE EFFECTS AGAINST CENTRAL-NERVOUS-SYSTEM TRAUMAAND ISCHEMIA

A series of 2,3-dihydro-5-benzofuranamines (5-aminocoumarans) were dev eloped for the treatment of traumatic and ischemic central. nervous sy stem (CNS) injury. Compounds within this class were extremely effectiv e inhibitors of lipid peroxidation in vitro and antagonized excitatory behavior coupled with peroxidative injury induced by spinal intrathec al injection of FeCl2 (mouse-FeCl2-it assay) in vivo. Selected compoun ds were tested for antagonistic activity on methamphetamine (MAP)-indu ced hypermotility resulting from dopamine release in the mouse brain. Among the compounds synthesized, compound 26n -[(4-phenyl-1-piperidiny l)meth]-5-benzofuranamine) exhibited potent effects in these assays (i nhibition of lipid peroxidation, IC50 = 0.07 mu M; mouse-FeCl2-it assa y, ID50 = 10.4 mg/kg, po; MAP-induced hypermotility, 98% inhibition, 1 0 mg/kg, ip). The S-(+)-form of compound 26n dihydrochloride (TAK-218) , which has 30 times more potent antagonistic activity on MAP-induced hypermotility than the R-(-)-form, improved more significantly the sur vival rate in the cerebral ischemia model (rat, 1-3 mg/kg, ip) during the period of 1-14 days after ischemia and decreased functional disord ers in the traumatic brain injury model (rat, 0.1-1 mg/kg, ip) 3-14 da ys after injury. These results imply a role for dopamine in deteriorat ion of CNS function after ischemic and traumatic injury. TAK-218 is a promising compound for the treatment of stroke and CNS trauma and is n ow under clinical investigation.