Chapter 7

Adrenergic Drugs

Epinephrine or adrenaline Norepinephrine or noradrenaline belong to Catecholamines邻苯二酚 , 儿茶酚 :Catechol

epinephrine:R=CH3norepinephrine:R=H

HO

HO

NH

OH

R

• 肾上腺素能药物是对自主神经系统施加药理作用的物质之一

• 自主神经系统 : 包括神经和神经节，对心脏、血管、腺体、呼吸系统、内脏器官和运动肌提供神经支配。

• Adrenergic drugs exert pharmacological effects on autonomic nervous system.

• Autonomic nervous system: Including the nerves and ganglia, control the heart, blood vessels, glands, respiratory system, visceral organs and the sports muscle.

• Epinephrine was found tobe the active comound in the early 20th century. In 1940s, norepinephrine was recognized as the real neurotransmitters in the peripheral nervous system.

7.1 The biosynthesis, metabolism and acting mechanism of Catecholamines such as norepinephrine and epinephrine

• Noradrenaline is the main neurotransmitters released by adrenergic nerve endings, the content in the nerve endings is about 3-300 times than in the cells.

• Norepinephrine can bind withα or βadrenergic receptor reversibly, promote the effector to produce physiological effects.

The biosynthesis and metabolism of noradrenaline (1)

L-tyrosine dopa dopamine

HO

NH2HO

OH

HO

NHCH3HO

OH

HO

NH2HO

HO

COOH

NH2

HO

HO

COOH

NH2

The biosynthesis and metabolism of noradrenaline (2)

• MAO(Monoamine oxidase)• COMT(Catechol-O-methyltransferase)• AR(aldehyde reductase )• AD (aldehyde dehydrogenase)

HO

NHCH3HO

OH

HO

NH2HO

OH

HO

CHOHO

OH MAO

HO

NH2CH3O

OH

COMT

7.2 Adrenergic drugs

• 1. α-receptor or α-, β-receptor agonists

(1) α-receptor agonists

Norepinephrine Bitartrate

• R-(-)-4-(2- 氨基 -1- 羟基乙基 )-1,2- 苯二酚 R,R-2,3- 二羟基丁二酸盐一水合物• R-(-)-4-(2-Amino-1-hydroxyethyl)-1,2-benzene

diol R,R-2,3-dihydroxy-butanedionate (1:1) salt monohydrate

CH2NH2

C OHH

OH

OH

CH OH

COOH

C HHO

COOH

H2O

receptor agonist, slight effective to receptor.

• A strong vasoconstriction.

• Increase the blood pressure, treat shock

• activity of (-)-body is 27 times than (+)-body.

• heat for 3 minutes at 120 or heat with concentrated ℃sulfuric acid at 80 ~ 90 for 2 hours, racemization will ℃be occurred;

• norepinephrine is easily oxidized under light or air, so it should be preserved without contacting with air.

• norepinephrine will be oxidized into norepinephrine red in the buffer solution of pH 6.5 added with iodine solution, sodium thiosulfate can fade the colour of iodine solution and then change into red.

( 二 ) α- 、 β- 受体激动剂1 ．肾上腺素 Epinephrine

• R-4-[( 甲胺基 )-1- 羟基乙基 ]-1,2 苯二酚• Although there is no oral adrenergic activity, the cli

nical use is much borader than norepinephrine.

OHNHCH3HO

HO

• α-receptor agonist, contract blood vessels, increase blood pressure.For emergency treatment of anaphylactic shock;

• β1-receptor agonist, excite cardiac muscle. treatment of cardiac arrest;

• β2- receptor agonist, relax bronchia. Remission of asthma

2 ．麻黄碱 Ephedrine

• Ephedrine is seperated from several Ephedra plants. in 1887, isolated from the Chinese herb Ephedra and pure Ephedrine was crystallized. Its clinical application was earlier than norepinephrine and epinephrine

(-)ephedrine* (-)pseudo~ (+)ephedrine (+)pseudo~ (1R,2S) (1R,2R) (1S,2R) (1S,2S)

化学结构： 1. 与肾上腺素相比，增加 CH3 ，没有 3,4- 二羟基 2. 有 2 个手性 C ， 4 个异构体用途 : 与肾上腺素相似 , 支气管舒张；血管升压；心脏兴奋剂；鼻充血治疗药

C OHH

C NHCH3H

CH3

C OHH

C HCH3HN

CH3

C HHO

C HCH3HN

CH3

C HHO

C NHCH3H

CH3

Structure-Activity Relationship( 一 ) 苯乙醇胺的基本结构

1. R1: -H αreceptor

-CH3 α,βreceptor

-CH(CH3)2 ， -C(CH3)3 βreceptor

OH

NR1

R2

H1

2

R3

• 2. R2: -H ， -CH3 （ 手性碳 , 如麻黄缄）• 3. R3: a. 3,4- 二羟基是基本结构 , 易被氧化； b. 无羟基 , 活性低 , 较稳定； c. 3-CH2OH, 4-OH; 3,5- 二羟基 ( 口服 )

d. 酯化 , 前药

OH

NR1

R2

H1

2

R3

Receptor and activity

Αreceptor, norepinephrine, increase blood pressure and resist shock

α/βreceptor, epinephrine, 同上 ; 兴奋心脏 , 舒张支气管α2 receptor, methyldopa, decrease the blood pressure

β1 多巴酚丁胺 强心药

β2 沙丁胺醇 舒张支气管 , 哮喘

Stability: auto-oxidation

• Reducibility of Phenolic substances is different by different conditions. in alkaline medium, phenoxy anion accelerate the auto-oxidation, wheras in acidic medium, reducibility is decreased.

• 去甲肾上腺素、肾上腺素、异丙肾上腺素易生成红色色素，并可进一步聚合成棕色多聚物。

racemization of carbon-2

• aqueous solution of norepinephrine and epinephrine will reduce the efficacy by the reason of recemization. Heating or acidic (pH4) conditions, the recemization will be speeded.

HO

C CH2NHCH3HO

OH

H

H

OH

HO CH2NHCH3

HO

C

Adrenergic Antagonists

• 1. Α-receptor antagonist

• (A) short-acting type

• (B) long-acting type

α1-receptor blocking agents: Prazosin is the first α1 - receptor antagonist, antihypertensive agents

• 母核为喹唑啉 ; 4 －氨基， 6,7 －二甲氧基 ; • 2- 位与 1- 哌嗪的氮相连联； • 4- 哌嗪的氮与羰基、呋喃的 2- 位相连

N

N

CH3O

CH3O

NH2

N N C

O

O

analogs: 哌唑嗪 ; 特拉唑嗪 ; 曲马唑嗪 ; 美他唑嗪 ; 多沙唑嗪

R 基团的不同，使它们的药动学性质有很大的差异

R

CH OCH3

CH3CH3

CH3

OCH2 C

OH

O

O

O

O

N

N

CH3O

CH3O

NH2

N N C

O

R =

;

;

;;

receptor antagonist(1) The development of -receptor antagonist

CH3

CH3Cl

Cl

CH

OH

CH2NHCH

Pronethalol

• 用碳桥替代 DCI 中 3,4 二氯得丙萘洛尔， 1962 年曾作为临床候选药物，因动物试验发现致癌， 1963 年即被撤消

CH CH2NHCH

OH

CH3

CH3

The first successful clinical -antagonist---Propranolol

• 芳环和侧链之间插入 氧亚甲基（ OCH2 ），• 将侧链从萘环的位移至位

O N

CH3

CH3

OHH

• Propranolol: for the treatment of a variety of cardiovascular diseases.

• First for angina pectoris,laterly as anti-arrhythmic drugs, in clinical practice found the anti-hypertensive activity.

-antagonist---Substituted at c-4 of aromatic ring---Practolol

• Selectively inhibit the excitement of heart;

• This discovery led to new understanding: - not all the antagonist are same.

HOH

CH3

CH3

O N

HN CH3

O

General rules: drugs substituted at C-4 are selective β- antagonists

• Genaral -antagonists:With 2- receptor antagonis

t activity,with the side effect of causing asthma• Selective -antagonists:with high selectively for β-

1 receptors of heart.

Propranolol

• R = 2,3- 取代的苯基 ;• R’ = -CH(CH3)2;• 无选择性

O N

CH3

CH3

OHH

Bisoprolol

• R = 4- 取代的基团 ;

特异性最高的 1- 受体阻断剂之一 ;

• 为强效、长效 1- 受体阻断剂，普萘洛尔的 4 倍；

(CH3)2CH2CH2OCH2 OCH2CHCH2NHCH(CH3)2

OH

2. Structure-Activity Relationship  1. the basic structure of -antagonist

• 取代的芳基 ;• 氧亚甲基 ;• 异丙肾上腺素 侧链 (N- 烷基 略有差别）

HOH

CH3

CH3

O N

R

2. 侧链的 SAR

• Hydroxyl and amino on side chains is the important receptor-binding group.

• Isopropyl or tertbutyl substituents on amino is better for β - receptor binding.

HOH

CH3

CH3

O N

R

3. 氧亚甲基的 SAR:Enhance the activity

conformation of the aromatic ring, hydroxyl and amino overlaping completely will consistent with the space requirements for the receptor-binding.

Öصþ

CH3

HN

CH3

OHO

NCH3

CH3

OHHO

NCH3

CH3OH

H

4. 取代芳基的 SAR

Benzene substituted at C-4: with good selectivity toβ1 - receptor, known as selective β1 – antagonist.

Benzene Substituted at C-2 and 3: non-selective to β receptor, known as the general β- antagonist

HOH

CH3

CH3

O N

R