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Here, we explored the possible interaction between duloxetine and SEP-363856 (SEP-856) in depression-related reactions. The results showed that oral administration of duloxetine showed powerful antidepressant-like effects in both the forced swimming test (FST) and the suspension tail test (TST). SEP-856 orally administered alone also exerted an antidepressant-like effect in FST and TST, especially at doses of 0.3, 1, and 10 mg/kg. In addition, duloxetine (15 mg/kg) and SEP-856 (15 mg/kg) both showed antidepressant-like effects in the sucrose preference test (SPT). Most importantly, in the above experiments, compared with duloxetine alone, the simultaneous use of duloxetine and SEP-856 caused a more significant antidepressant-like effect. It is worth noting that doses of drug combination in FST and TST did not change the motor activities of mice in the open-field test (OFT). Thus, duloxetine and SEP-856 seem to play a synergistic role in regulating depression-related behaviors and might be beneficial for refractory depression.

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one ( 6j ) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D 2 , D 3 , and serotonin 5-HT 1A , 5-HT 2A receptors, but was also endowed with low to moderate activities on 5-HT 2C , α 1 , and H 1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.