1-OXA-3,8-DIAZASPIRO[4.5]DECAN-2-ONE DERIVATIVES WITH A POTENT INHIBITORY EFFECT ON NEURAL CA-UPTAKE AND PROTECTING ACTION AGAINST TET-INDUCED BRAIN EDEMA AND MEMORY AND LEARNING-DEFICITS

A series of novel 1-oxa-3,8-diazaspiro[4.5]decan-2-one derivatives 8-7 1 were synthesized. Several representatives were examined for their in vitro inhibitory action on Ca-45-uptake into cerebrocortical synaptos omes depolarized by potassium and veratrine and on triethyltin-induced brain edema. Of the compounds displaying most potent inhibitory actio n on veratrine-induced Ca-45-uptake into cerebrocortical synaptosomes and outstanding protection against triethyltin chloride (TET) induced brain edema in rats, four were tested for their antihypoxic action and prevention of learning and memory deficits elicited by various agents leg, electroshock, diazepam, scopolamine, carbon dioxide and normobar ic hypoxia). In some of these tests the four compounds showed remarkab le protecting/restoring activity. It is assumed that the beneficial ef fects of these compounds in brain edema formation are probably related to their actions on intracellular Ca2+- and Na+-movements. These cell ular effects may also play role in their antiamnesic actions, but othe r mechanisms may also be involved. On the basis of results obtained in the tests used, the pharmacological profile of the novel 1-oxa-3,8-di azaspiro [4.5]decan-2-one derivatives seems to differ from that of kno wn Ca2+-antagonists such as flunarizine or nimodipine and Na+-channel blocker, phenytoin. Out of the four most active compounds tested, one (44) was selected for further investigation and this compound is curre ntly under preclinical development with the code name of RGH-2716 or T DN-345.