Synthesis and biological evaluation of novel 3,4-diaryl lactam derivatives as triple reuptake inhibitors

A series of 3,4-diarylpyrrolidin-2-one was designed, prepared and evaluated as triple reuptake inhibitors for antidepressant. Most compounds exhibited comparable in vitro efficacy as norepinephrine and dopamine transporter reuptake inhibitors. Especially, 2i showed better potency than GBR-12909 (IC₅₀ = 14 nM) which was used as reference compound for dopamine transporter. In addition, 2a and 2b showed inhibition (5.17 μM–85.6 nM) for three transporters.     

In vitro structure–activity relationships of aplysinopsin analogs and their in vivo evaluation in the chick anxiety–depression model

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT_2B and 5-HT_2C receptor subtypes, with selectivity for 5-HT_2B over 5-HT_2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with K_i’s as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety–depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.     

超声在围绝经期妇科疾病诊断中的作用研究

目的:探讨超声在围绝经期妇科疾病诊断中的作用,为临床诊断提供依据.方法:选取2012年2月至2012年8月间于我院接受诊断和治疗的处于围绝经期的阴道不规则出血患者128例,观察超声诊断与病理学诊断的差异,分析超声诊断的作用.结果:超声诊断与病理学检查结果的总符合率为95.31％,内膜良性病变类型与内膜癌和癌前病变类型的平均内膜厚度均明显高于内膜生理变化类型(P＜0.05),子宫内膜厚度≥10mm的发生内膜良性病变或内膜癌及癌前病变的64例(66.67％),厚度＜10 mm的患者发生内膜良性病变或内膜癌及癌前病变10例(31.25％),差异有统计学意义(P＜0.05).结论:超声在围绝经期妇科疾病诊断中的作用显著,值得在临床上推广应用.     

Psychological distress and personality factors in takotsubo cardiomyopathy

Background

Takotsubo cardiomyopathy (TCC) is a transient condition characterised by severe left ventricular dysfunction combined with symptoms and signs mimicking myocardial infarction. Emotional triggers are common, but little is known about the psychological background characteristics of TCC. This study examined whether patients with TTC have higher levels of psychological distress (depressive symptoms, perceived stress, general anxiety), illness-related anxiety and distinct personality factors compared with healthy controls and patients with heart failure.

Methods and Results

Patients with TCC (N = 18; mean age 68.3 ± 11.7 years, 77.8?% women) and two comparison groups (healthy controls: N = 19, age 60.0 ± 7.6, 68.4?% women and patients with chronic heart failure: N = 19, age 68.8 ± 10.1, 68.4?% women) completed standardised questionnaires to measure depression (PHQ?9), perceived stress (PSS-10), general anxiety (GAD-7), illness-related anxiety (WI-7) and personality factors (NEO-FFI and DS-14). Psychological measures were obtained at 23 ± 18 months following the acute TTC event. Results showed that patients with TCC had higher levels of depressive symptoms (5.2 ± 5.2 vs. 2.5 ± 2.4, p = 0.039) and illness-related anxiety (2.1 ± 1.7 vs. 0.7 ± 1.3, p = 0.005) compared with healthy controls. Patients with TCC did not display significantly elevated perceived stress (p = 0.072) or general anxiety (p = 0.170). Regarding personality factors, levels of openness were lower in TCC compared with healthy controls (34.2 ± 4.3 vs. 38.2 ± 5.6, p = 0.021). No differences between TCC and heart failure patients were found regarding the psychological measures.

Conclusions

TCC is associated with higher levels of depressive symptoms, more illness-related anxiety and less openness compared with healthy controls. These data suggest that TCC is associated with adverse psychological factors that may persist well after the acute episode.

     

Focus: Sex and Gender Health: Associations of Gender,Smoking, and Stress with Transitions in Major Depression Diagnoses

Using data from the newly available U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; Wave 3; n = 36,309), we evaluated relationships among gender, cigarette smoking status (current, former, non-smoker), life event stress (0-1 vs. 2+ events), and their impact on transitions in major depression diagnosis (MDD; new vs. absent cases; ongoing vs. remit cases). Women who were both current and former cigarette smokers with more than two stressful events had higher rates of new MDD diagnosis compared to men who were current or former smokers with two or more stressful events. Current smoking and experiencing two or more stressful events increased the odds of having an ongoing MDD diagnosis, while being a former smoker decreased these odds. Results suggest that smoking and stress are markers for depression risk in women and should help guide clinical assessment as well as gender-difference research on the biological underpinnings of these conditions.     

N-Alkylated arylsulfonamides of (aryloxy)ethyl piperidines: 5-HT7 receptor selectivity versus multireceptor profile

The N-alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT₇ receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl-N-{1-[2-(2-(t-butyl)phenoxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), a potent and selective 5-HT₇ receptor antagonist and 33 (1-methyl-N-{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT_2A/5-HT₇/D₂ receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED = 1.25 mg/kg and 1 mg/kg, ip, respectively). These findings warrant further studies to explore the therapeutic potential of N-alkylated arylsulfonamides for the treatment of CNS disorders.     

Design,synthesis and biological evaluation of novel serotonin and dopamine receptor ligands being 6-bromohexyl saccharine derivatives

Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT_1A (compound 18, K_i = 4 nM – antagonist mode) and D₂ (compound 15, K_i = 7 nM – antagonist mode) receptor, and in some cases also 5-HT₇ receptor (compound 17, K_i = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors.     

舒肝解郁胶囊联合阿戈美拉汀对抑郁症患者血清单胺类神经递质和神经功能相关因子的影响

摘要 目的：观察舒肝解郁胶囊联合阿戈美拉汀治疗抑郁症的疗效及对血清单胺类神经递质和神经功能相关因子的影响。方法：纳入我院2017年5月~2020年5月接诊的120例抑郁症患者,经双色球随机分组法将患者分为对照组和观察组,各为60例。对照组患者予以阿戈美拉汀治疗,观察组患者予以舒肝解郁胶囊联合阿戈美拉汀治疗。比较两组疗效、血清单胺类神经递质、神经功能相关因子、抑郁焦虑评分及不良反应发生率。结果：观察组的临床总有效率为93.33%（56/60）,高于对照组的73.33%（44/60）（P<0.05）。两组治疗6周后汉密尔顿抑郁量表（HAMD）、汉密尔顿焦虑量表（HAMA）评分较治疗前降低,且观察组较对照组低（P<0.05）。两组治疗6周后多巴胺（DA）、去甲肾上腺素（NE）、5-羟色胺（5-HT）水平较治疗前升高,且观察组高于对照组（P<0.05）。两组治疗6周后S100?茁、髓磷脂碱性蛋白（MBP）、神经元特异性烯醇化酶（NSE）水平较治疗前降低,且观察组低于对照组（P<0.05）。两组不良反应发生率对比无差异（P>0.05）。结论：舒肝解郁胶囊联合阿戈美拉汀治疗抑郁症,疗效显著,可有效调节血清单胺类神经递质和神经功能,改善抑郁症状,且安全可靠。     

Central GABAergic systems and depressive illness

Clinical depression and other mood disorders are relatively common mental illnesses but therapy for a substantial number of patients is unsatisfactory. For many years clinicians and neuroscientists believed that the evidence pointed toward alterations in brain monoamine function as the underlying cause of depression. This point of view is still valid. Indeed, much of current drug therapy appears to be targeted at central monoamine function. Other results, though, indicate that GABAergic mechanisms also might play a role in depression. Such indications stem from both direct and indirect evidence. Direct evidence has been gathered in the clinic from brain scans or postmortem brain samples, and cerebrospinal fluid (CSF) and serum analysis in depressed patients. Indirect evidence comes from interaction of antidepressant drugs with GABAergic system as assessed by in vivo and in vitro studies in animals. Most of the data from direct and indirect studies are consistent with GABA involvement in depression.     

Effect of prenatal stress and gonadal hormone condition on depressive behaviors of female and male rats

Whether prenatal stress (PNS) and gonadal hormones may influence depressive behavior of rats in the forced swim test was investigated. In Experiment I, adult diestrous female rats had increased immobility, which is indicative of depression, but did not show any significant difference in the duration of struggling compared to intact adult males. In Experiment 2, the behavior of adult intact, castrated, or castrated dihydrotestosterone (DHT)- or estrogen (E2)-replaced offspring of dams that were restrained under lights for 45 min on gestational day 18 (PNS) or were not subjected to gestational stress (non-PNS, control condition) were compared. There were no effects of PNS, but DHT and E2 produced anti-depressant effects on behavior of male rats. Castration decreased struggling and increased immobility compared to intact rats. DHT or E2 replacement was able to partially reinstate struggling and immobility behavior but not to levels of intact males. In Experiment 3, behavior of PNS or control rats that were in proestrus or were ovariectomized and DHT, E2, or vehicle-replaced were compared. Ovariectomy decreased struggling and increased immobility compared to that of proestrous rats. E2 or DHT to control females increased anti-depressant struggling behavior compared to ovariectomized control or PNS rats administered vehicle, which demonstrated greater duration of struggling than did E2-primed, PNS rats. E2 or DHT administration decreased immobility of PNS and control females. These findings suggest that E2 and DHT have some anti-depressant effects but that modest PNS may alter E2's ability to alleviate some depressive behavior in female, but not male rats.