Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d 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, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective To evaluate the cost-effectiveness of current universal infant rotavirus vaccination strategy,in China.Methods Through constructing decision tree-Markov model,we simulated rotavirus diarrhea associated cost and health outcome on those newborns in 2012 regarding different vaccination programs as:group with no vaccination,Rotavirus vaccination group and Rotateq vaccination group,respectively.We determined the optimal program,based on the comparison between incremental cost-effectiveness ratio (ICER) and China' s 2012 per capital gross domestic product (GDP).Results Compared with non-vaccination group,the Rotavirus vaccination and Rotateq vaccination groups had to pay 3 760 Yuan and 7 578 Yuan (both less than 2012 GDP per capital) to avert one disability adjusted life years (DALY) loss,respectively.Results from sensitivity analysis indicated that both results were robust.Compared with Rotavirus vaccination program,the Rotateq vaccination program had to pay extra 81 068 Yuan (between 1 and 3 times GDP per capital) to avert one DALY loss.Data from the sensitivity analysis indicated that the result was not robust.Conclusion From the perspective of health economics,both two-dose Rotarix vaccine and three-dose's Rotateq vaccine programs were highly cost-effective,when compared to the non-vaccination program.It was appropriate to integrate rotavirus vaccine into the routine immunization program.Considering the large amount of extra cost that had to spend on Rotateq vaccination program,results from the sensitivity analysis showed that it was not robust.Rotateq vaccine required one more dose than the Rotarix vaccine,to be effective.However,it appeared more difficult to practice,suggesting that it was better to choose the Rotarix vaccine,at current stage.