Design, Synthesis, and Evaluation of Non-Competitive NMDA Receptor Antagonists and Serotonergic Agents for Neuropsychiatric and Metabolic Disorders

Neuroplasticity is increasingly recognized as a central mechanism in the pathogenesis and treatment of neuropsychiatric disorders, particularly major depressive disorder. Alterations of the physiological neuroplasticity mechanisms leads to structural and functional damages in key areas of the brain, particularly the PFC and the hippocampus. A new class of rapid-acting antidepressants, including non-competitive NMDA receptor antagonists and serotonergic agents acting as 5-HT2A agonists, has shown the ability to restore neuroplasticity rapidly and durably, even in resistant patients. This project focused on the development of novel analogues and derivatives of methadone and psilocin. Methadone is currently used as a racemate for analgesia and opioid abuse management. The (S)-enantiomer, devoid of opioid activity, is under clinical investigation as a rapid-acting antidepressant. To overcome the inefficiency of traditional synthesis and chiral resolution, a new process based on a chiral cyclic sulfamidate was developed, affording enantiopure (R)- and (S)-methadone in high yield and optical purity. This route was extended for the preparation of 20 enantiopure methadone metabolites, whose pharmacological profiling revealed novel candidates with NMDA antagonism comparable or superior to methadone but improved receptor selectivity. Psilocin, a 5-HT2A agonist, is limited by instability, poor pharmacokinetics, intense psychedelic effects, and is usually administered as its prodrug psilocybin. To address these issues, a library of carbamate prodrugs was synthesized, achieving improved modulation of psilocin release and favorable in vivo properties. In addition, a fluorescent psilocin analogue was designed to probe intracellular mechanisms, supporting recent hypotheses of intracellular 5-HT2A signaling and vesicular accumulation. Finally, psilocin derivatives unable to cross the blood-brain barrier were prepared as potential treatments for peripheral metabolic diseases.