Synthesis and Evaluation of a Series of Piperidine‐2,6‐dione‐piperazine (piperidine) Derivatives as Multireceptor Atypical Antipsychotics

In this paper, we report the discovery and the synthesis of novel, potential antipsychotic piperidine‐2,6‐dione derivatives combining potent dopamine D 2 , D 3 and serotonin 5‐HT 1A , 5‐HT 2A , 5‐HT 2C receptor properties. We describe the structure–activity relationships that led us to the promising derivative: 1‐(4‐(4‐(6‐fluorobenzo[d]isoxazol‐3‐yl)piperidin‐1‐yl)butyl)‐4‐(4‐chlorophenyl)‐piperidine‐2,6‐dione 5 . The unique pharmacological features of compound 5 are a high affinity for dopamine D 2 , D 3 and serotonin 5‐HT 1A , 5‐HT 2A , 5‐HT 2C receptors, together with a low affinity for the H 1 receptor (to reduce the risk of obesity under chronic treatment). In a behavioral model predictive of positive symptoms, compound 5 inhibited apomorphine‐induced climbing behavior and MK‐801‐induced hyperactivity with no extrapyramidal symptoms liability in mice. In particular, compound 5 was more potent than clozapine.