Chapter 6 Central Nervous System Drugs. Shanghai Jiao Tong University Introduction neurons are lost...

Chapter 6 Central Nervous System Drugs

Shanghai Jiao Tong University

Introduction

neurons are lost either by necrosis or apoptosis. This category is typified by slow chronic disorders

Disorders

of the CNS

Psychiatric ：

neurodegenerative

Schizophrenia,depression,anxiety, obsessive, epilepsy , compulsive disorder (OCD),

attention deficit hyperactivity disorder (ADHD)

Synaptic dysfunction

(1) dysregulation of neurotransmitter availability

(2) signaling

Alzheimer’s disease

Parkinson’s disease


6.1 Schizophrenia

6.1.1 Mechanism of action:

精神分裂症病因：脑内多巴胺

神经系统功能亢进使脑部多巴胺过量或多巴胺受体超敏。

①Antagonism of dopamine-mediated synaptic neurotransmission

②Act at dopamine receptors in different brain regions

③Diminish dopamine synthesis and release

HO

HO

NH2


6.1.2 ‘Typical’ Antipsychotic Drugs (First-Generation)

1) Classification:

Phenothiazines: chlorpromazine( 氯丙嗪 )

perphenazine( 奋乃静 )

Thioxanthenes: chlorprothixene ( 氯普噻吨 )

Butyrophenones: haloperidol( 氟哌丁醇 )

substituted benzamides: sulpiride ( 舒必利 )

S

N Cl

N CH3

CH3

S

N

NN OH

CF3

S

Cl

N CH3

CH3

N

OHO

FCl

NH

O

OCH3

NSH2NOO

CH3


2) Stucture-activity Relationship of Tricyclic Anti- psychotics

Amine functionality (Site A)

Intervening alkyl chain (Site B)

Diaryl heterotricyclic (Site C),


A:

The size and nature of the basic amino group has considerable influence on the behavioral profile of the phenothiazine neuroleptics. A tertiary mine is optimal, both mono and desmethylchlorpromazine are several times less active than the parent molecule.

In many cases, larger N-alkyl groups decrease neuroleptic potency. The N-methylpiperazine compound prochlorperazine has enhanced potency, as do a number of other piperazines.

B:

The distance between Sites A and C is critical for neuroleptic activity, with a three carbon chain being optimal.

Shortening the chain to two carbons has the effect of amplifying the anticholinergic and antihistaminic properties.

Whereas small alkyl substituents such as methyl are tolerated at the C2 carbon, larger substituents (i.e., R = phenyl) that restrict the free rotation decrease neuroleptic potency.


C:

Introduction of other group VI elements in place of the sulfur in the phenothiazines produced the corresponding phenoxazine( 吩噁嗪 )and phenoselenazine( 吩硒嗪 )derivatives. The phenoxazines are markedly less active than the phenothiazines.The diminished activity of the phenoxazines may be a result of the shortened oxygen-carbon bond length, which would tend to pull the two aromatics closer together and at a tighter angle.

Replacement of the nitrogen within the phenothiazine ring system with a methane carbon. The introduction of the double bond within the propylamino chain provides for geometric isomers. The geometry, wherein the 2-substituted aromatic ring and the aminoethyl substructures are on the same side of the double bond, is referred to as "cis," and the isomers having this configuration have been shown to possess enhanced neuroleptic potency relative to the "trans." (for instance, chlorprothixene)


Chemical Name ： 2-Chloro-N,N -dimethyl-10 H-phenothazine-10-propanamine.hydrochloride (N， N- 二甲基 -2- 氯 -10 H- 吩噻嗪 -10- 丙胺盐酸盐 )

3) Phenothiazines


临床应用：多方面的药理作用，安定作用较强，治疗精神分裂症和狂躁症，亦用于镇吐、强化麻醉及人工冬眠等。

N

S

Cl

N

Cl NH2

+ Cl

OHO

Cu

150°C,pH 5-6Cl N

HO OH

Fe

200°C Cl NH

S, I2

170°CCl N

H

S Cl N

NaOH , D N

S

Cl

N

HCl

N

S

Cl

N

.HCl

Synthesis route


Metabolism

NH

SHO

Cl

O

NH

S

Cl

O

N

S

Cl

OHO

N

SHO3SO

Cl

N

S

Cl

N

SHO

Cl

N

N

SO

Cl

NH2

NH

N

OH

N

S

N

SO O

O


Analogues:

Perphenazine( 奋乃静） Fluphenazine （氟奋乃静）

N

S

Cl

N NOH

2

5

10N

S

F3C

N NOH

2

5

10

N

S

NN

OR

FF

F

N

S

NN

O

FF

F

O

N

S

NN

O

FF

F

O

庚酸酯癸酸酯

long acting drugs


4 ） Chlorprothixene Structure： doublebond

Propylamino chain provides for geometric isomers

"cis" isomer having enhanced neuroleptic potency relative to the "trans."

S

N

Cl

S

N

Cl

S

Cl

N

Action: 与 Chlorpromazine 相似用于伴有抑郁和焦虑的精神分裂症–更年期抑郁症–焦虑性神经官能症。


5 ） Butyrophenones

【 Haloperidol 氟哌啶醇】

Chemical Name ： 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)butan-1-one, 4-[4-(4- 氯苯基 )-4- 羟基 -1- 哌啶基 ]-1-(4- 氟苯基 )-1- 丁酮

N

OHO

F

Cl

ActionHaloperidol is an antipsychotic with actions most closely resembling those of phenothiazines with a piperazine side-chain.


Synthesis route

Cl

NHO

F

OF

OCl

Cl

NHHO

+

FCl

OCl

AlCl3 F

OCl

Cl

CH2

CH3

Cl

O

NHH3CCH2O

NH4ClCl

NHHCl 1) HBr/CH3COOH

2) H2O / NaOH

Cl

NHHO

NH2 CH2=CHCOOCH3 NCOOCH3

COOCH3

1) CH3ONa

2) HClN O

COOCH3

HCl N O

ClBr

Mg, HCl

NOH

Cl

1) H2/Pt -C

2) HCl Cl

NHHO


6.1.3 ‘Atypical’ Antipsychotic Drugs (Second-Generation)

Higher antagonist affinity at the 5HT2A receptor relative to the D2 receptor has been proposed to distinguish atypical from typical antipsychotic drugs. as 5HT2A inverse agonists ( 反向激动剂） .

There also may be important differences between typical and atypical drugs in striatal D2 receptor occupancy relative to extrastriatal D2 receptor occupancy. Typical antipsychotic drugs appear to preferentially interact with striatal D2 receptors while atypical antipsychotic drugs have a complex pattern of effects on extrastriatal ( 纹状体外） D2 receptors.

经典的抗精神病药具有广泛的拮抗多巴胺受体作用，产生锥体外系副作用，主要表现为：类似帕金森症的运动障碍；坐立不安，不停地动作；震颤、僵硬等。


【 Clozapine 氯氮平】

NH

NN

Cl

NCH3

Chemical Name8-Chloro-11-(4-methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine ，8- 氯 -11-(4- 甲基 - 哌嗪基 -1- 基 -)-5H- 二苯并 [b,e][1,4] 二氮杂


Synthesis route

NH2

Cl NO2

+Cl

H3COOC ClNO2

HN

COOCH3

[Cu]HN N CH3

ClNO2

HN

N

N

O

CH3

ClNH2

HN

N

N

O

CH3

H2 POCl3

Cl

HN

N

NCH3

N

ActionA atypical antipsychotics. It has relatively weak dopamine receptor-blocking activity at D1, D2, D3, and D5 receptors but has a high affinity for the D4 receptor. It is also a serotonin (5HT) antagonist, with strong binding to 5-HT2A/2C receptor subtype. It has a clear lower risk of inducing EPS (extrapyramidal symptoms) ( 锥体外系症状）


奥氮平（ Olanzapine ）礼来公司－ Zyprexa®

本品是在氯氮平的结构基础上开发的新药，对纹状体D2 受体抑制作用明显低于使用氟哌啶醇，作用与氯氮平相当。它的粒细胞缺乏症的发生率低于氯氮平。锥体外系副作用发生率低。

本品起效迅速（ 1 周即可见效），无须逐步递增剂量，每日只需给药 1 次，过量时无生命危险。

奥氮平其化学结构与氯氮平接近，保持了氯氮平的治疗效果，尤其是对难治性的精神分裂症有一定的疗效。

NH

N

S

Cl

NN


6.2 Affective Disorders: Depression and Bipolar

6.2.1 Introduction ：

Major depression is a chronic disorder. The World Health Organization (WHO) has estimated that approximately 121 million individuals worldwide suffer from depression and that depression will become the primary disease burden worldwide by 2020.

Affective Disorders:

Dysthymia is a less severe form of depression involving long-term, chronic symptoms that do not disable but keep individuals from functioning well or from feeling good.

Bipolar affective disorder (BPAD)

is a common, recurrent ( 反复发生） , and severe psychiatric disorder characterized by episodes of mania ( 狂躁性发作） , depression, or mixed states (simultaneously occurring manic and depressive symptoms).


HO

HO

OH

NH2

NH

HONH2

6.2.2 Biochemical mechanisms for depression treatment :

The monoamine theory of depression and drugs acting on monoamine neurotransmission has dominated the treatment of depression.

Molecular cloning has allowed the pharmacological and structural characterization of a large family of related genes encoding Na+/Cl- dependent neurotransmitter transporters (SCDNTs).

Dopamine transporter (DAT),

Norepinephrine transporter (NET),

Serotonin transporter (SERT))

Norepinephrine(NE) serotonin transporter (SE,5-HT)


6.2.3 Classifacation of antidepressant drug 1)Selective norepinephrine reuptake inhibitors (SNRIs)

去甲肾上腺素重摄取抑制剂 Imipramine ( 丙咪嗪 ) Amitriptyline ( 阿米替林 )

2)Selective serotonin reuptake inhibitors （ SSRIs ）选择性 5- 羟色胺重摄取抑制剂 Fluoxetine ( 氟西汀 ) Sertraline ( 舍曲林 )

3) Monoamine oxidase inhibitors: MAOIs 单胺氧化酶抑制剂 Moclobemide ( 吗氯贝胺 ) Toloxatone ( 托洛沙酮 )

HN

O

Cl

NO

NO

HOCH3

O

N

NCH3

CH3 NCH3

CH3

O

F3C

HNCH3

HN CH3

Cl

Cl


6.2.4 Stucture-activity Relationship of Tricyclic anti- depressants(TCAs)

All the ‘classical’ TCAs have a basic three-ring pharmacophore.

The substitution of the sulfur bridge of the phenothiazine ring of promethazine with an ethylene bridge resulted in imipramine, the first clinically useful TCA. It did not take long for medicinal chemists focusing on the diamine structure to substitute the additional N–CH2

group in imipramine for a C=CH group in amitriptyline.

The monomethyl amine derivatives of dimethylamine, eg., desipramine and nortriptyline were also effective.

N

NH

CH3 NH

CH3

Desipramine( 地昔帕明 )

(Dibenzazepines)

Nortriptyline( 去甲替林 )

Dibenzocycloheptens)


【 Imipramine 丙咪嗪】

N

N

CH3

CH3

3-(10,11-Dihydro-5H-dibenz[b,f]azepin-5-yl)propyldimethylamine

3-(10,11- 二氢 -5H- 二苯并 [b,f] 氮杂 -5- 基 )- 丙基二甲基胺

ActionImipramine is a representative TCAs which show polypharmic target profiles. But imipramine is less sedating and has moderate antimuscarinic activity.


Synthesis route

NH

N

1. LiNH3

2.Cl N

CH3

CH3 NCH3

CH3

N

NCH3

CH3

HCl

NH2 NH2NO2 NO2

CH3

NO2

CH3ONa

HCOOC2H5

Fe/HCl

Metabolism

N

N

N

NH

N

NH2

N

NH

OH

N

N

OHHO

N

NH

OHHO


6.2.5 Selective Serotonin-reuptake inhibitors

Fluoxetine(氟西汀 ) 礼来公司－百优解 ® （ Prozac® ）

N-Methyl-3-[4- trifluoromethyl)phenoxy] -benzenepropanamine hydrochloride

O

F

F

F

NH2 .HCl *

选择性 5- 羟色胺重摄取抑制剂（ SSRI ）提高 5- 羟色胺在突触间隙中的浓度，而改善病人的情绪 , 用于抗抑郁，择性强与三环类抗抑郁药相比疗效相当，较少抗 M 受体的副作用和较少心脏毒性， 110 个国家和地区上市， 3800 万患者服用

Chapter 6 Central Nervous System Drugs. Shanghai Jiao Tong University Introduction neurons are lost...

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