DIZOCILPINE (MK-801) DERIVATIVES AS NEUROPROTECTIVE NMDA RECEPTOR ANTAGONISTS WITHOUT PSYCHOMIMETIC SIDE EFFECTS

N-methyl-D-aspartate receptors (NMDARs) mediate excitatory neurotransmission and are involved in neurological disorders such as Alzheimer’s disease, epilepsy, and autism. Open-channel blockers such as dizocilpine (MK-801) effectively inhibit NMDAR activity, but their therapeutic use is limited by severe psychotomimetic side effects that arise from slow unbinding kinetics.
Here, we characterized 27 novel dibenzo[a,d][7]annulene derivatives designed to improve the safety profile of NMDAR blockers. Electrophysiological screening in HEK293 cells expressing human GluN1/GluN2A or GluN1/GluN2B receptors identified K2056 as a highly potent inhibitor (submicromolar IC₅₀ values) and K1949 as a moderate inhibitor. Both compounds inhibited GluN1/GluN2A and GluN1/GluN2B, subtypes that are essential for brain development and synaptic plasticity. In addition, both derivatives showed reduced cytotoxicity, supporting their potential as safer candidates.
In vivo, both K1949 and K2056 crossed the blood–brain barrier, and 10 mg/kg was identified as the no-observed-adverse-effect level (NOAEL). At this dose, neither compound induced hyperlocomotion in the open-field test nor impaired prepulse inhibition in rats, adverse effects typically observed with MK-801. Moreover, K1949, but not K2056, significantly reduced hippocampal damage in a rat model of NMDA-induced neurodegeneration.
These findings indicate that dibenzo[a,d][7]annulene analogs of dizocilpine represent promising NMDA receptor antagonists with reduced psychotomimetic liability. In particular, K1949 emerges as a neuroprotective lead candidate and K2056 as a highly potent blocker, supporting further development of these compounds for the treatment of Alzheimer’s disease and other NMDAR-related neurological disorders.