新型抗精神病药物盐酸鲁拉西酮的合成研究进展

盐酸鲁拉西酮是一种新型的抗精神病药物。归纳了该原料药的合成方法,根据起始原料的光学纯度、中间体的不同可将合成路线分为三大类,并且对这三类方法进行了比较分析,总结出各自的优缺点,从而为该原料药的制备研究提供参考。     

Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study

Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague–Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.     

常见抗精神病药物的合成及应用进展

对传统的抗精神病药氯丙嗪、氟哌啶醇和舒必利,以及以利培酮、奥氮平、半富马酸喹硫平、齐拉西酮、阿立哌唑、鲁拉西酮为代表的新型抗精神病药物的合成方法和应用进行了总结,并对以鲁拉西酮为先导化合物的新型抗精神病药的设计进行了展望。     

Ziprasidone: Pharmacological and clinical profile of the newest atypical antipsychotic.

Notes that ziprasidone is the 5th atypical antipsychotic to be approved by the Food and Drug Administration for the treatment of schizophrenia. Since 1989, when the first atypical agent was introduced to the US market, clinical use of these compounds has progressed to the point that several atypical agents are considered first-line treatment for schizophrenia. This article reviews pharmacological and clinical aspects of ziprasidone to familiarize clinicians who will encounter its use. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antipsychotic-like behavioral effects and cognitive enhancement by a potent and selective muscarinic M? receptor agonist, AC-260584.

AC-260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one) is a potent and selective muscarinic M? receptor agonist. AC-260584 was evaluated in animal models: antipsychotic-like effects were tested by the ability to reduce amphetamine- and MK-801-induced hyperactivity and apomorphine-induced climbing; catalepsy was assessed by measuring step-down latency; spatial memory was tested by using the Morris water maze. AC-260584 reduced amphetamine- and MK-801-induced hyperactivity and apomorphine-induced climbing. In contrast to haloperidol, AC-260584 did not produce catalepsy. AC-260584 enhanced performance in the water maze during a probe test without a platform after 6 days of training, similar to the positive control tacrine. These data indicate that AC-260584 has a behavioral profile consistent with antipsychotic-like efficacy with the potential to improve cognitive performance and shows reduced liability for extrapyramidal symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

载脂蛋白E基因多态性与利培酮所致体质量降低的关联研究

目的: 探讨载脂蛋白E（apolipoprotein E，APOE）基因多态性与精神分裂症（schizophrenia，SZ）患者抗精神病药物治疗所致体质量变化的关联。方法: 调查并随访1 516例首发SZ患者使用利培酮、阿立哌唑、喹硫平、氯氮平、奥氮平、奋乃静治疗2至7周后的体质量变化。使用TaqMan基因分型技术检测APOE基因多态性，应用Cox比例风险模型分析APOE基因变异与SZ患者药物治疗所致体质量变化之间的关系。结果: 研究结果显示，在使用利培酮药物治疗患者中，rs7412位点相加模型增加体质量降低风险，HR（95%CI）为1.78（1.01-3.14），P=0.045。在使用利培酮药物治疗患者中，rs405509位点AC/CC基因型携带者相比AA基因携带者体质量降低的风险升高，HR（95%CI）为1.75（1.02-2.98），P=0.04。在除利培酮以外的其他药物治疗患者中，未发现rs769450，rs7412和rs405509不同基因型（相加模型、显性模型和隐性模型）与体质量增加、体质量降低的发生风险存在统计学关联，P值均>0.05。分层分析结果显示，在基线体质量正常组以及基线体质量超重或肥胖中，rs7412和rs405509不同基因型（相加模型、显性模型和隐性模型）与体质量降低的发生风险无异质性，P值均>0.05。结论: APOE基因rs7412和rs405509位点变异增加了SZ患者服用利培酮所致体质量降低的风险；临床应关注基线体质量正常患者APOE基因rs7412 C>T、rs405509A>C变异与利培酮所致体质量降低。     

Haloperidol induced microcatalepsy differs in CD-1, BALB/c, and C57BL/6 mice.

The degree of arrest of movement (microcatalepsy) induced by haloperidol at doses equipotent for operant rate suppression was measured with computerized instrumentation. The inbred C57BU6 mouse strain displayed more susceptibility to microcatalepsy than the CD-1 and BALB/c strains. In addition, the C57BL/6 strain exhibited a greater degree of sensitization to repeated dosing than did the other 2 strains. The results were consistent with the C57BL/6 mouse's hypodopaminergic profile reported in the literature but were at odds with results reported for conventional catalepsy testing. The C57BL/6 mouse may serve as a model for genetic vulnerability to extrapyramidal motor side effects and may be useful in quantifying the mild extrapyramidal motor side effects of atypical antipsychotic drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Assessment of the Effects of Dietary Vitamin D Levels on Olanzapine-Induced Metabolic Side Effects: Focus on the Endocannabinoidome-Gut Microbiome Axis

Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different combinations of vitamin D levels and atypical antipsychotic drug (olanzapine) exposure on whole-body metabolism and the eCBome-gut microbiota axis in female C57BL/6J mice under a high fat/high sucrose (HFHS) diet in an attempt to identify a link between the latter and the different metabolic outputs induced by the treatments. Olanzapine exerted a protective effect against diet-induced obesity and insulin resistance, largely independent of dietary vitamin D status. These changes were concomitant with olanzapine-mediated decreases in Trpv1 expression and increases in the levels of its agonists, including various N-acylethanolamines and 2-monoacylglycerols, which are consistent with the observed improvement in adiposity and metabolic status. Furthermore, while global gut bacteria community architecture was not altered by olanzapine, we identified changes in the relative abundances of various commensal bacterial families. Taken together, changes of eCBome and gut microbiota families under our experimental conditions might contribute to olanzapine and vitamin D-mediated inhibition of weight gain in mice on a HFHS diet.     

齐拉西酮的合成

以3-氯-1,2-苯并异噻唑和无水哌嗪为原料合成1-(1,2-苯并异噻唑-3-基)哌嗪(2),以6-氯-1,3-二氢-吲哚酮和氯乙酰氯为原料经Friedel-crafts酰化制备5-(2-氯乙酰基)-6-氯-1,3-二氢-吲哚酮(3),3经硼氢化钠和三氟乙酸还原制得5-(2-氯乙基)-6-氯-1,3-二氢-吲哚酮(4),2和4在碘化钠/碳酸钠的水溶液中缩合得到齐拉西酮(1),总收率50.5%(以3-氯-1,2-苯并异噻唑计,n/n)。齐拉西酮的结构经IR和1H NMR确证。