title: Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics.
abstract: The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1A and 5-HT2A receptor properties, are the focus of the present article. The most-promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia.
authors.affiliation: Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.forename: Songlin
authors.initials: S
authors.lastname: Wang
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Xu
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Minquan
authors.initials: M
authors.lastname: Yu
authors.forename: Song
authors.initials: S
authors.lastname: Zhao
authors.forename: Shicheng
authors.initials: S
authors.lastname: Liu
authors.forename: Yinli
authors.initials: Y
authors.lastname: Qiu
authors.forename: Tan
authors.initials: T
authors.lastname: Zhang
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* / Q000494:pharmacology / Q000633:toxicity; D001362:Avoidance Learning / Q000187:drug effects; D001682:Biological Availability; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D007928:Lethal Dose 50; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011388:Prolactin / Q000097:blood; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D015430:Weight Gain / Q000187:drug effects
chemical_list: C582926:7-(4-(4-(6-fluorobenzo(d)isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one; D014150:Antipsychotic Agents; D003374:Coumarins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007555:Isoxazoles; C000606913:KCNH2 protein, human; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D044282:Receptor, Serotonin, 5-HT1A; D011388:Prolactin