Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists

In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX₂R subtype and culminating in the discovery of 23, a highly potent, OX₂R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX₁R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.     

血府逐瘀丸治疗老年2型糖尿病伴失眠的临床疗效及其对认知功能的影响

目的:探究血府逐瘀丸治疗老年2型糖尿病伴失眠患者的临床疗效及其对认知功能影响。方法:选取43例我院收治的老年2型糖尿病伴失眠患者,将其随机分为实验组及对照组。对照组21例予地西泮治疗,实验组22予血府逐瘀丸治疗。观察两组治疗前后失眠症状及认知功能的变化情况。结果:治疗后,实验组总有效率(86.4%)高于对照组(61.9%),其差异经比较有统计学意义(P0.05);两组匹兹堡睡眠质量指数量表(PSQI)评分均较治疗前显著降低(P0.05),与对照组相比,实验组PSQI评分较低(P0.05),空腹血糖水平较低(P0.05),蒙特利尔认知评估量表(MoCA)评分较高(P0.05)。结论:血府逐瘀丸可有效降低老年2型糖尿病伴失眠患者的血糖水平,提升睡眠质量,改善失眠及认知功能障碍。     

不同方法治疗飞行人员慢性失眠症的疗效比较

目的:飞行人员中睡眠问题发生率高,影响白天工作效能,危及飞行安全,寻找安全有效治疗方法为保证飞行十分必要,本实验观察不同治疗方法在治疗飞行人员慢性失眠的临床疗效,为飞行人员慢性失眠的临床治疗提供一种安全有效的措施。方法:将我院自2007年至2013年收治的52例飞行人员中的慢性失眠患者,排除严重影响睡眠的器质性疾病,随机分为舒乐安定组、中药治疗组和耳针及生物反馈联合治疗组。分别在治疗前、治疗结束后第2天采用匹兹堡睡眠质量指数(PSQI)对患者的睡眠质量进行评价。结果:治疗结束后3组PSQI均较治疗前均有所改善,其中舒乐安定治疗组优于中成药及耳针及生物反馈联合治疗组,差别有统计学意义(P0.05),中成药物治疗组与耳针及生物反馈联合治疗组无明显统计学差异(P0.05)。但对于重度的睡眠障碍,单独采用舒眠胶囊或生物反馈治疗,治疗效果欠佳。结论:舒乐安定治疗失眠疗效确切,但由于其影响工作效能,危及飞行安全较少使用,中成药物、耳针及生物反馈治疗安全有效,病人易于接受,是较好的治疗飞行人员慢性失眠的方法。     

Age‐Related Differences in the Lifestyle Regularity of Seniors Experiencing Bereavement,Care‐Giving,Insomnia, and Advancement Into Old‐Old Age

Compared to younger adults, seniors (≥60 yrs) often adopt a highly regular lifestyle, perhaps as an adaptive response to age‐related changes in their sleep and circadian rhythms. At baseline, diary measures of lifestyle regularity (SRM‐5) were obtained from 104 seniors of three separate groups. Thirty‐three subjects were challenged by spousal bereavement or the need to care for a spouse at home with dementia (Challenged); 33 were suffering from formally diagnosed (DSM‐IV) insomnia (Insomnia); and 38 were healthy, well‐functioning older seniors in the second half of their eighth decade of life or later (Healthy Older). The objective of this study was to determine whether lifestyle regularity increased as a function of age within each of these three senior groups. Overall, age was significantly correlated with SRM‐5 (r=0.41, p<0.001), with the SRM score increasing by 0.67 units/decade. The same was true for the Challenged and Insomnia groups, which also showed a significant correlation between SRM and age (Challenged: r=0.48, p<0.01; Insomnia: r=0.36, p<0.05), though with a slightly faster rate of SRM increase in the Challenged (0.95 units/decade) than Insomnia (0.55 units/decade) group. Perhaps there was no correlation between age and SRM (r=0.07, n.s.) in the Healthy Older group due to the small age range, although this group did have a higher overall SRM score than the other two groups (p<0.01). The study thus confirmed that the previously observed increase in lifestyle regularity over the adult lifespan persists into later life. This may represent an adaptive behavioral response that might be used in future therapeutic approaches.     

Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX₁R/OX₂R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.     

Health-Related Quality of Life in Adolescent Chronotypes—A Model for the Effects of Sleep Problems,Sleep-Related Cognitions,and Self-efficacy

In adolescence, the circadian preference shifts toward eveningness orientation. Eveningness seems to be negatively correlated with quality of life. The present study investigates influencing factors of this association and proposes a model for the mediating effects of sleep, sleep-related cognitions, and self-efficacy according to chronotype. The sample comprised N?=?280 adolescents (172 girls) aged 14–16 yrs (mean?=?15.19, SD?=?.76). Circadian preference, health-related quality of life (HRQoL), sleep disturbances, sleep-related dysfunctional cognitions, and general perceived self-efficacy were assessed online. Morning-orientated adolescents reported significantly higher HRQoL and less insomnia symptoms compared with evening-oriented chronotypes. In the total sample, insomnia symptoms mediated the relationship of chronotype and HRQoL. The strongest predictor of HRQoL in evening types was the degree of sleep-related dysfunctional cognitions. HRQoL in morning types was most strongly predicted by general self-efficacy, i.e., the global confidence in coping abilities. The findings support a negative relationship of eveningness and HRQoL in adolescents. Insomnia symptoms were identified to be mediating factors in this relationship. The influence of the mediating factors on HRQoL differed between morning and evening types. The model provides implications of how to enhance HRQoL in adolescents according to their circadian preference. (Author correspondence: karolin.roeser@uni-wuerzburg.de)     

灵龟八法结合火针对失眠患者睡眠质量及炎性因子水平的影响

目的:探讨灵龟八法结合火针对失眠患者睡眠质量及炎性因子水平的影响。方法:选取2017年5月～2019年3月期间空军杭州特勤疗养中心收治的失眠患者97例,根据数字表法将患者分为对照组(n=48,常规针刺治疗)和研究组(n=49,灵龟八法结合火针治疗),比较两组患者治疗4周后的临床疗效,比较两组治疗前、治疗4周后的中医症状积分、炎性因子水平,比较两组治疗前、治疗2周后、4周后的睡眠质量,记录两组治疗期间不良反应情况。结果:研究组治疗4周后的临床总有效率为93.88%(46/49),高于对照组的72.92%(35/48)(P0.05)。两组治疗4周后难以入寐、多梦易醒、头晕、心悸的症状积分均下降,且研究组低于对照组(P0.05)。两组治疗2周后、4周后匹兹堡睡眠质量指数(PSQI)评分均较治疗前降低(P0.05),研究组治疗4周后PSQI评分较治疗2周后降低(P0.05),研究组治疗4周后PSQI评分低于对照组(P0.05)。两组治疗4周后血清白介素-1β(IL-1β)、白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平均下降,且研究组低于对照组(P0.05)。治疗期间对照组不良反应发生率为12.50%(6/48),研究组不良反应发生率为16.33%(8/49),两组不良反应发生率对比无统计学差异(P0.05)。结论:灵龟八法结合火针治疗失眠患者,疗效显著,可改善患者临床症状,提高睡眠质量,并降低机体炎性因子水平,且安全性较好,具有一定的临床应用价值。     

Discovery of spiropiperidine-based potent and selective Orexin-2 receptor antagonists

To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC(50) value of 3nM with 450-fold selectivity against Orexin-1 Receptor (OX1R).     

Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists

During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration.     

Influence of pKa on the biotransformation of indene H1-antihistamines by CYP2D6

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H₁-antihistamines. Reductions in pK_a via incorporation of a β-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.