Interestingly, deuterium substitution in compound 7, initially expected to enhance stability, did not significantly alter its metabolic profile due to metabolic switching, where deuteration redirects biotransformation pathways rather than universally slowing metabolism. Given the key role of excitotoxicity in AD pathogenesis, this study also explored NMDAR inhibition. All tested derivatives exhibited inhibitory activity toward the GluN1/GluN2B receptor. Among them, compound 5m demonstrated voltage-independent inhibition, emerging as the most potent NMDAR antagonist in the series. Based on these findings, compound 5m was identified as the lead candidate and advanced to in vivo pharmacokinetic studies. The results confirmed its BBB permeability, with a brain-to-plasma ratio indicative of efficient CNS penetration. Importantly, no acute toxicity was observed at therapeutic doses, supporting its potential for further development as an MTDL for AD therapy. This study underscores the importance of optimizing lipophilicity, metabolic stability, and target selectivity in the development of CNS-active ChEIs and NMDAR antagonists. The findings suggest that THA-based MTDLs represent promising multifunctional therapeutics for AD, warranting further preclinical validation and structural optimization to enhance efficacy and safety.