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

Sigma-1 receptor (<i>σ</i> ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one <i>O</i>-(2-aminoethyl) oxime derivatives were synthesized. <i>In vitro</i> biological evaluation led to the identification of <b>1a</b>, <b>14a</b>, <b>15d</b> and <b>16d</b> as the most high-affinity (<i>K</i> _i < 4 nmol/L) and selective <i>σ</i> ₁R agonists. Among these, <b>15d</b>, the most metabolically stable derivative exhibited high selectivity for <i>σ</i> ₁R in relation to <i>σ</i> ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, <b>15d</b> also exhibited high brain permeability and excellent oral bioavailability. Importantly, <b>15d</b> 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, <b>15d</b> produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, <b>15d</b> inhibited GSK3<i>β</i> and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these <i>in vivo</i> proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating <i>σ</i> ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of <b>15d</b> renders it a promising candidate for treating schizophrenia.