title: Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics.
abstract: A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China; Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China.
authors.forename: Xiao-Wen
authors.initials: XW
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China. Electronic address: leifu@sjtu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
authors.affiliation: Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, PR China. Electronic address: lijianqb@126.com.
authors.forename: Jian-Qi
authors.initials: JQ
authors.lastname: Li
mesh_terms: D000577:Amides / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D014150:Antipsychotic Agents; D010879:Piperazines; D011956:Receptors, Cell Surface; D000077489:Piperazine
keywords: Atypical antipsychotic; Dopamine; Multireceptor; Serotonin; X-ray crystallography