Discovery and proof-of-concept study of a novel highly selective sigma-1 receptor agonist for antipsychotic drug development.

Sigma-1 receptor ( R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one -(2-aminoethyl) oxime derivatives were synthesized. biological evaluation led to the identification of , , and as the most high-affinity ( < 4 nmol/L) and selective R agonists. Among these, , the most metabolically stable derivative exhibited high selectivity for R in relation to R and 52 other human targets. In addition to low CYP450 inhibition and induction, also exhibited high brain permeability and excellent oral bioavailability. Importantly, demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, inhibited GSK3 and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of renders it a promising candidate for treating schizophrenia.