title: Synthesis and evaluation of a series of piperidine-2,6-dione-piperazine (piperidine) derivatives as multireceptor atypical antipsychotics.
abstract: 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.
authors.affiliation: Department of Systems Biology, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Xu
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Bi-Feng
authors.initials: BF
authors.lastname: Liu
authors.forename: Guisen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D010880:Piperidines; D011954:Receptors, Dopamine; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; C032727:piperidine; D016291:Dizocilpine Maleate; D003024:Clozapine; D001058:Apomorphine