Explorations into Eszopiclone

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Outlines

Introduction SAR and Synthesis Mechanism and drug effect Clinical application and Side effects Prospects of Eszopiclone

and Comparison between similar drugs

Introduction SAR Synthesis The separation of enantiomers

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Introduction of Eszopiclone Eszopiclone belongs to the group of medicines called central

nervous system (CNS) depressants (medicines that make you drowsy or less alert).

This medicine is used to treat insomnia (trouble in sleeping, helping you get to sleep faster and sleep through the night.

The Enationmers

Zopiclone was produced and developed by Rhdne-poulenc company in France.

It hit the French market in 1987 with its commercial name “Imovane”.

Eszopiclone The S-enantiomer of zopicl

one Eszopiclone was approved

by the US Food and Drug Administration on December 15, 2004, for the treatment of insomnia in patients aged _>18 years.

Its commercial name is “Lunesta”.

Before the development of zopiclone, there are many sedative-hypnotic drugs which are used for the treatment of insomnia.

These drugs include antihistamines, sedating anti-depressants, neuroleptics, benzodiazepines, non-benzodiazepine receptor agonists and melatonin.

Benzodiazepines

Although the structure of zopiclone is quite different with that of benzodiazepines, it can bind with benzodiazepine receptors and has similar pharmacoactivity with benzodiazepines.

Since its side effects are much fewer than benzodiazepines, it is categorized to the third generation of sedatives .

BACK

pyrrolo-piperazine ring

5-choloro pyridine ring

carbonyl group piperazine formyl grou

p

Well suited to the receptor

form a hydrogen bond with

the receptor (C=0……

HX)

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Synthesis of Zopiclone

Derivatives

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Studies show that the affinity of (S)-zopiclone to the receptor is 1000 times larger than (R)-zopiclone, and (R)-zopiclone has nearly no sedative and hypnotic effects.

As a result, scientists began to study the ways that they can ge

t the pure (S)-enationmer of zopiclone.

Separation of Enationmers The most widly applied

method is the Stereospecific liquid chromatography using chiral static phase.

Although this method is easy to process, the chiral colum is much too expensive and exaust quickly.

Separation of Enationmers Capillary electrophoresis β － cyclodextrin as the chi

ral solvating agent The bezene ring which is co

nnected with the chiral carbon atom of zopiclone can insert into the cavity of the cylodextrin and the groups with higher polarity can form hydrogen bounds with the –OH on the cylodextrin molecules.

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The mechanism and drug effect of eszopiclone

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Mechanism Effect

A brief look at eszopiclone nonbenzodiazepine sedative-hypnotic ag

ent

Binding site on GABA receptor

2.1 mechanism of eszopiclone

2.1.1 classification of GABA receptor

GABAA

GABAc

GABAB

structurally related ligand-gated ion channels

second messenger systems by G proteins

Modulated by Ca2+ and K+ channel

2.1.2 action of eszopiclone on GABAA receptor The mechanism is similar with benzodiaz

epine drugs GABAA receptor is classfied into 7 isoforme

rs:(αβγθδπε) Most forms are composed of αβγsubunits

benzodiazepine bind to BZ1 and BZ2 receptor (α,γ2)

↓Increase the affinity of GABA to its receptors (α,β) ↓enhances the channel opening effect ↓ Cl-influx into the neuronal cell ↓creating a hyperpolarized cell membrane that prev

ents further excitation.

2.1.3Difference of Eszopiclone binds the different area of the same

receptors different configuration more selective

Unfortunately,eszopiclone’s exact mechanism of action in enhancing and promoting sleep is unknown.

2.2 drug efficacy of eszopiclone

2.2.1 drug effect Now,eszopiclone is approved for the treatment of insomnia only .

Researches about major depressive Disorder, rheumatoid( 风湿 ) arthritis( 关节

炎 ) ,menopause( 更年期 ) and obstructive sleep apnea( 阻塞性睡眠呼吸暂停 ) are still carrying on

On the whole, it significantly improved sleep efficiency, sleep latency, wake time after sleeping onset, number of awakenings, number of nights awakens weekly, total sleep time andquality and depth of the sleep.

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Clinical efficacy

Adverse Reactions

Pharmacokinetics

Dosage and Directions魏雪莹 0440123

benzodiazepine

(1) Residual effects

(2) Forgotten effect

(3) Withdrawal effects

(4) Addiction and

dependence

An ideal sedative-hypnotic drugs

to induce sleep rapidly; to not affect sleep architecture; no drug residues effect the next day; to not affect memory function, including

without forgotten symptoms; to not inhibit respiration; no drug-dependent or withdrawal symptoms

in Long-term use; with no interaction with alcohol and other

drugs.

Clinical efficacy

transient insomnia LPS, WASO, NAW, time to sleep onset

sleep efficiency,sleep quality,TST

well tolerated

unpleasant taste

chronic insomnia

WASO, LPS TST,sleep efficiency,daytime functio

n No tolerance and no adverse Unpleasant taste

chronic insomnia in the elderly

Sleep latency, WASO TST,quality of sleep,depth of sleep No adverse events and well tolerance Unpleasant taste

treatment of insomnia caused by other diseases ,MDD

improve sleep latency, TST, WASO ,

quality of sleep and daytime function

well tolerated

recovery rate of treatment of

depression

Conclusion

Sleep latency,WASO,NAW TST,sleep quality,daytime ability of function,dayt

ime alterness,sense of physical No withdrawal effects or addiction and depende

nce

Adverse Reactions

Unpleasant taste

headache , somnolence,

abnormal dreams , and dizziness

a minor memory impairment

Pharmacokinetics

Tmax ＜ 1h t1/2 = 6 h

weakly bound to plasma protein metabolized by oxidation and demet

hylation

Direction and dosage 1, 2, and 3 mg adult 18 ～ 64 elderly patients severe hepatic impairment pregnancy or lactation temperance

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失眠药物治疗进展失眠药物治疗进展以及同类药物间的比较以及同类药物间的比较

0440105 单纯

一、失眠药物治疗进展1 、传统的镇静催眠药 巴比妥类

（司可巴比妥，速可眠） 苯二氮卓类

（三唑仑）（三唑仑）

一、失眠药物治疗进展

2 、新型镇静催眠药物 已批准上市 ：

唑吡坦 zolpidem （ 1988 年）

扎来普隆 zaleplon （ 1999 年）

左旋佐匹克隆 zopiclone （ 2005 年）

一、失眠药物治疗进展3 、临床研究中的催眠药 Indiplon （注册前阶段 ）

加波沙朵 Gaboxadol （ 3 期临床研究阶段 ）

褪黑素 Melatonin

二 、 同类药物间的比较1 、传统的镇静催眠药 20 世纪 60 年代以前：巴比妥类药物

治疗指数低，依赖性和戒断症状严重

苯二氮卓类药物（ BZD ） 药效学耐受

20 世纪 80 年代：非苯二氮罩类药物

依赖性和戒断症状较轻， BZD 合适的替代品

二 、 同类药物间的比较2 、新一代治疗失眠药物比较 唑吡坦

αl 一 GABA(A ）受体、较 BZ 类药物的副作用小 佐匹克隆

引起 GABA 介导的神经元抑制、与 BZ 类相似的催眠作用

扎来普隆GABAA 复合物 α 亚单位上的 ω1 受体、与 BZ 类相似的催眠效果，中枢性副作用更小

二 、 同类药物间的比较3 、新型催眠药物临床研究比较 Indiplon

能够选择性地作用于 GABA 一 A 受体的特定亚型、改善各年龄患者的各种失眠症状

Gaboxadol （加波沙朵）选择性突触外 GABA 一 A 激动剂

二 、 同类药物间的比较

3 、新型催眠药物临床研究比较 Eszopiclone

试验结果表明， eszopiclone 在没有残留效应的情况下，能够促使患者快速入睡和维持睡眠稳定。目前，没有一种药物在没有残留效应的情况下能显示促进催眠和维持睡眠的效果。

二 、 同类药物间的比较总结：

第三代镇静催眠药服用方便、口服吸收好，半小时达血液浓度高峰，药物代谢排泄快，经肾脏代谢。本类药物治疗指数高，基本不改变正常的生理睡眠结构，不易产生耐受性、依赖性。

佐匹克隆具有良好的催眠效果，不良反应较小，撤药反应与失眠反跳现象较少。适用于各种原因引起的失眠，尤其是无法耐受 BZD 类催眠药物残余作用的病人；可以作为 BZD 的替代药物，代替或交替应用。在短期用药上，佐匹克隆已逐渐取代 BZD ，但在长期用药上还需进一步研究。

vitamin C vitamin C ＝ ＝ sleep pill sleep pill ？？

Q & AQ & A

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