Dizocilpine derivatives with neuroprotective effect lacking the psychomimetic side effects

Abstract

We aimed to prepare novel dibenzosuberane derivatives that act on N-methyl-D-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Ourin silicoanalyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds3land6fto penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy,6fshowed high relative inhibition (∼90% for GluN1/GluN2A), while3lshowed moderate inhibition (∼50%). Anin vivotoxicity study determined that compounds3land6fwere safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound3lat a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzosuberane derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.