THE EFFECTS OF SB 206284A, A NOVEL NEURONAL CALCIUM-CHANNEL ANTAGONIST, IN MODELS OF CEREBRAL-ISCHEMIA

The effects of SE 206284A, 1-[7-(4-benzyloxyphenoxy)heptyl] piperidine hydrochloride, have been investigated in vitro on calcium and sodium currents in rat-cultured dorsal root ganglion (DRG) neurones and potas sium-mediated calcium influx in rat synaptosomes. Cardiovascular hemod ynamic effects in both anesthetized and conscious rats, and neuroprote ctive activity in in vivo cerebral ischemia models were also investiga ted. In the rat DRG cells, SE 206284A caused almost complete block of the sustained inward Ca2+ current (IC50 = 2.4 mu M), suggesting that t he compound is an effective blocker of slowly inactivating, high-volta ge calcium current. SE 206284A reduced locomotor hyperactivity in the gerbil bi-lateral carotid artery occlusion model without affecting isc hemia-induced damage in the hippocampal CAI region. In the rat middle cerebral artery occlusion model, SE 206284A reduced lesion volume in t he posterior forebrain, and in the rat photochemical cortical lesion m odel, lesion volume was reduced even when treatment was delayed until 4 hours after occlusion. At neuroprotective doses, SE 206284A had no c ardiovascular effects. These findings show that SE 206284A is a novel calcium channel antagonist that shows neuroprotective properties.