Lipase mediated resolution of γ-azidoalcohols in aqueous and organic media: Synthesis of (R)- and (S)-fluoxetine and duloxetine

A simple and efficient method for the synthesis of optically active γ-azidoalcohols is described. The lipase catalyzed kinetic resolutions of acetates of γ-azidoalcohols in aqueous as well as organic media have been studied. The enantiomerically pure γ-azidoalcohols obtained by the kinetic resolution in high enantiopurity have been utilized towards the synthesis of enantiomeric pairs of anti-depressant drugs, fluoxetine and duloxetine.     

小醒脑针刺法联合度洛西汀对持续性姿势-知觉性头晕患者心理状态、平衡功能及睡眠质量的影响

摘要 目的：探讨小醒脑针刺法联合度洛西汀对持续性姿势-知觉性头晕（PPPD）患者心理状态、睡眠质量及平衡功能的影响。方法：收集2017年1月~2019年6月期间我院收治的70例PPPD患者为研究对象。按门诊号单双数将研究对象分为对照组（n=35,度洛西汀治疗）和研究组（n=35,小醒脑针刺法联合度洛西汀治疗）,对比两组头晕发作频次、头晕发作持续时间以及眩晕残障程度评定量表（DHI）评分、汉密尔顿抑郁量表（HAMD）评分、汉密尔顿焦虑量表（HAMA）评分、Berg平衡量表（BBS）评分、活动平衡信心量表（ABC）评分、微觉醒指数、入睡后清醒时间、睡眠分期转换次数、醒转次数、匹兹堡睡眠质量指数（PSQI）评分。结果：两组治疗后头晕发作频次、头晕发作持续时间、微觉醒指数、入睡后清醒时间、睡眠分期转换次数、醒转次数以及DHI、PSQI、HAMA、HAMD评分均较治疗前降低,且研究组较对照组低（P<0.05）。治疗后两组BBS、ABC评分均较治疗前升高,且研究组较对照组高（P<0.05）。结论：小醒脑针刺法联合度洛西汀治疗PPPD患者,可有效改善患者眩晕症状、心理状态、睡眠质量及平衡功能。     

Chemoenzymatic synthesis of (S)-duloxetine using carbonyl reductase from Rhodosporidium toruloides

A chemoenzymatic strategy was developed for (S)-duloxetine production employing carbonyl reductases from newly isolated Rhodosporidium toruloides into the enantiodetermining step. Amongst the ten most permissive enzymes identified, cloned, and overexpressed in Escherichia coli, RtSCR9 exhibited excellent activity and enantioselectivity. Using co-expressed E. coli harboring both RtSCR9 and glucose dehydrogenase, (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol 3a was fabricated with so far the highest substrate loading (1000 mM) in a space-time yield per gram of biomass (DCW) of 22.9 mmol L⁻¹ h⁻¹ g DCW⁻¹ at a 200-g scale. The subsequent synthetic steps from RtSCR9-catalyzed (S)-3a were further performed, affording (S)-duloxetine with 60.2% overall yield from 2-acethylthiophene in >98.5% ee.     

Antagonism of Serotonin 5-HT1A Receptors Potentiates the Increases in Extracellular Monoamines Induced by Duloxetine in Rat Hypothalamus

Abstract: In the current study we examined the effects of coadministration of a serotonin 5-HT_1A antagonist, (±)-1-(1 H -indol-4-yloxy)-3-(cyclohexylamino)-2-propanol maleate (LY 206130), and a dual 5-HT and norepinephrine (NE) uptake inhibitor, duloxetine, on extracellular levels of NE, 5-HT, dopamine (DA), 5-hydroxyindoleacetic acid, and 3,4-dihydroxyphenylacetic acid in rat hypothalamus microdialysates. LY 206130 (3.0 mg/kg, s.c.) alone significantly increased NE and DA levels by 60 and 34%, respectively, without affecting 5-HT levels. Duloxetine administration at 4.0 mg/kg, i.p. alone produced no significant changes in levels of 5-HT, NE, or DA. In contrast, when LY 206130 and duloxetine were coadministered at 3.0 mg/kg, s.c. and 4.0 mg/kg, i.p., respectively, 5-HT, NE, and DA levels increased to 5.7-, 4.8-, and threefold over their respective basal levels. These data demonstrate that antagonism of somatodendritic 5-HT_1A autoreceptors and concomitant inhibition of 5-HT and NE uptake with duloxetine may promote synergistic increases in levels of extracellular 5-HT, NE, and DA in hypothalamus of conscious, freely moving rats.     

A Generalised Increase in Protein Carbonyls in the Brain in Parkinson''s but Not Incidental Lewy Body Disease

Abstract: A serotonin (5-HT)_1A receptor partial agonist, buspirone, potentiates the clinical antidepressant properties of 5-HT reuptake inhibitors (SSRIs). Herein, we examined the interaction of buspirone with two SSRIs, duloxetine and fluoxetine, on extra-cellular levels of 5-HT, dopamine (DA), and noradrenaline (NAD) in single dialysate samples of freely moving rats. Duloxetine (5.0 mg/kg, s.c.) and fluoxetine (10.0 mg/kg, s.c.) increased dialysate levels of DA (65 and 60% vs. basal values, respectively), NAD (400 and 90%, respectively), and 5-HT (130 and 110%, respectively) in the frontal cortex (FCX). Buspirone (2.5 mg/kg, s.c.) similarly elevated levels of DA (100%) and NAD (160%) but reduced those of 5-HT (−50%). Administered with buspirone, the ability of duloxetine and fluoxetine to increase 5-HT levels was transiently inhibited (over 60 min), although by the end of sampling (180 min) their actions were fully expressed. In contrast, buspirone markedly and synergistically facilitated the elevation in DA levels elicited by duloxetine (550%) and fluoxetine (240%). Furthermore, buspirone potentiated the induction of NAD levels by duloxetine (750%) and fluoxetine (350%). These data suggest that a reinforcement in the influence of SSRIs on DA and, possibly, NAD but not 5-HT release in FCX may contribute to their increased antidepressant activity in the presence of buspirone. More generally, they support the hypothesis that a reinforcement in dopaminergic transmission in the FCX contributes to the actions of SSRIs and other antidepressant drugs.