Medicinal Chemistry Chapter 3 Peripheral Nervous System Drugs.

Medicinal ChemistryChapter 3

Peripheral Nervous System Drugs

Outline

Drug Affecting Cholinergic Neurotransmission

Cholinergic Drugs

Anticholinergic Drugs

Drug Affecting Adrenergic Neurotransmission

Adrenergic Drugs (agonist)

Adrenergic Antagonist (Chapter 4)

Antihistamines Histamine H1 Receptor Antagonists

Local Anesthetics

3.1 Cholinergic Drugs （拟胆碱药）

ON

O

Aceylcholine

• Cholinergic effect Mediated by acetylcholine （ ACh）

Biosynthesis of Acetylcholine

HOCOOH

NH2

Serinedecarboxylase

HONH2 HO

N

ON

O

Choline N-methyltransferase

Cholineacetyltransferase

Aceylcholine

The Classification of Cholinergic Drugs

Acetylcholinesterase inhibitors (AChEIs)

Cholinocepter agonists

Cholinergic Drugs

3.1.1 Cholinocepter agonists( 胆碱受体激动剂 )

Cholinergic receptor

• M-receptor Muscarine ( 毒蕈碱 )

• N-receptor Nicotine ( 烟碱 )

ON

HO

N

N

Cholinocepter agonists

NO NH2

OCl

Carbachol (卡巴胆碱)

NO NH2

OCl

Bethanechol Chloride (氯贝胆碱)

ON

HO

Muscarine

ON

O

Aceylcholine

SAR of Cholinocepter agonists

O CH2 CH2 N(CH3) ClH3C

O

Acyloxy group

Ethylene group

Quaternary ammonium

Ing’s rule of five:

This rule suggests that there should be no more than five atom between the nitrogen and the terminal hydrogen atom for maximal muscarinic potency.

• 1. The molecule possesses a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt.

• 2. For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of methyl group.

• 3. The molecule should have an oxygen atom, preferably an ester-like oxygen, capable of participating in a hydrogen bond.

• 4. There should be a two-carbon unit between the oxygen atom and the nitrogen atom.

O CH2 CH2 N(CH3) ClH3C

O

Acyloxy group

Ethylene group

Quaternary ammonium

R1 ON

O R4

carbamoyl substitution is stable;Et or Ph substitutionlower activity

R2

R3

R2=Me, decrease N-effectM-effect retains

R3=Me, inhibit AChEN-effect > M-effect

cation is important

As+(CH3)3, S+(CH3)2,

Se+(CH3)2 subtitution

decrease the acitivity

Me> H and bulky group

Triethyl substitution displays anticholinergic effect

Bethanechol Chloride （氯贝胆碱）

2-[(Aminocarbonyl)oxy]-N,N,N-trimethyl-1-propanaminium chloride

(S)-Bethanechol Chloride

N

O NH2

O

H

CH3

N

O NH2

O

H3C

H

(R)-Bethanechol Chloride

>

240 fold

NO NH2

OCl

CH3

NO

O

Bethanechol Chloride

*

Actions and Uses

• Potent muscarinic agonist. Orally effective, also administered by subcutaneous ( 皮下 ) injection.

• Increased hydrolytic stability (carbamate and steric bulk)

• Stimulant of GI tract smooth muscle and urinary bladder.

• Uses: For the relief of post-surgical urinary retention （尿潴留） and abdominal distention （腹胀） .

• Low toxicity, no serious side effects.

• Should be used with caution in asthmatic （ 哮 喘的） patients.

Bethanechol Chloride

ClOH COCl2

ClO

O

Cl NH3, EtOHCl

O

O

NH2

N(CH3)3N

O

O

NH2

Cl

Synthesis:

Future Muscarinic Agonists

N NS

O

N

Xanomeline

Current research interest is focused on developing agents with selective affinity for muscarinic receptors in the brain. Potentially useful in the treatment of Alzheimer’s disease （ 阿 尔 茨 海 默 尔 ） and other cognitive disorders. e.g. Xamomeline ( 呫诺美林 )

3.1.2 Acetylcholinesterase Inhibitors (AChEIs)

H3C ON(CH3)3

O

Aceylcholine

H3C OH

O

HON(CH3)3+

AChE

H2O

Acetylcholinesterase (AChE)

Inhibition of acetylcholinesterase (AChE) increases the concentration of acetylcholine (ACh) in the synapse. This results in prolonging the action of ACh, producing both muscarinic and nicotinic responses.

Therapeutic Application of AChEIs

• Treatment of myasthenia gravis ( 重症肌无力 ), atony （弛缓） in the gastrointestinal tract and glaucoma （青光眼） .

• Investigational therapy for Alzheimer’s disease

• Agricultural insecticides and nerve gas warfare agents.

• Indirect acting cholinergic agonists

Reversible AChEIs

N N

CH3

CH3

CH3

O

O

CH3NH

Physostigmine 毒扁豆碱

O N(CH3)2

N(CH3)3

O

Br

N

O N(CH3)2

O

BrCH3

Neostigmine bromide 溴新斯的明

Pyridostigmine bromide溴吡斯的明

N

NH2

Tacrine他克林

O

CH2

CH3O

CH3O

N CH2

HCl

Donepezil (Aricept)多奈哌齐

O NN

H3C

CH3

CH3

O

CH3

CH3

Rivastigmine (Exelon)卡巴拉汀

• Classical AChEIs

• Nonclassical AChEIs

Neostigmine Bromide （溴新斯的明）

O N(CH3)2

N(CH3)3

O

Br

1 2

3

3-[[[(Dimethylamino)carbonyl]oxy]-N,N,N-trimethylbenzenaminium bromide

Actions and Uses

• Chemically more stable than physostigmine （毒扁豆碱）

• Longer duration of action

• Administered orally or iv

• The most frequent use of neostigmine is to prevent atony ( 张力迟缓 ) of the intestinal, skeletal, and bladder musculature. Also used as urinary stimulant.

Tacrine （他克林）

N

NH2

•Potent centrally acting AChE inhibitor

• FDA approved for the treatment of Alzheimer’s Disease

(To increase ACh levels in the brain)

• Side Effects: Hepatotoxicity; Abdominal cramping （腹部绞痛）

New Non-Competitive AChEIs

•Exhibit greater CNS AChE selectivity

•Little or no hepatotoxicityO

CH2

CH3O

CH3O

N CH2

HCl

Donepezil (多奈哌齐)

O NN

H3C

CH3

CH3

O

CH3

CH3

Rivastigmine (利斯的明)

O

NCH3

CH3O

Galantamine （加兰他敏）

3.2 Anticholinergic Drugs （抗胆碱药）

• Muscarinic antagonists

• Nicotinic antagonists

• Neuromuscular blocking agents (N2-receptor) 神经肌肉阻断剂

• Ganglionic blocking agents （ N1-receptor ）神经节阻断剂

3.2.1 Muscarinic antagonists

• Muscarinic antagonists are compounds that have high affinity for M-receptor but have no intrinsic activity.

Competitive (reversible) antagonists of ACh•Antagonism responses include: decreased

contraction of GI and urinary tract smooth muscles, dilation of pupils ( 扩 张 瞳 孔 ), reduced gastric secretion, decreased saliva （唾液） secretion.

Therapeutic Uses of Muscarinic antagonists

• Treatment of smooth muscle spasms ( 肌痉挛 )

• Ophthalmologic （眼科） examinations• Treatment of gastric ulcers ( 胃溃疡 )

• Reduction of nasal and upper respiratory tract secretions in cold and flu

Solanaceous Alkaloids （茄生物碱类）

NH3C

H

O

O

O

NH3C

H

O

O

CH2OH

Atropine (阿托品) Scopolamine (东莨菪碱)

CH2OH

**

Found mainly in henbane ( 花 烟 草 ) (Hyoscyamus niger, 莨 菪 属 ), deadly nightshade ( 龙 葵 属 植 物 ) (Atropa belladonna, 颠 茄 ), and jimson weed (Datura stramonium ，曼陀罗叶 )

• Belladonna Alkaloids: esters of tropic acid and tropine.• Parenteral preparations (quaternary derivatives) are more potent than the parent compounds.• Therapeutic uses: mydriatic （ 扩 瞳 药） ; antispasmodic （解痉药） .• Side effects: dryness of mouth; urine retention （ 尿 潴 留） ; blurred vision （ 视 力 模糊） ; constipation （便秘） .• Atropine is an antidote （ 解 毒 药 ） to poisoning by organophosphorus pesticides （有机磷农药） .

Atropine Sulfate

.H2SO4. H2O

2

NCH3

H

O

O

HOH .

12

3456

7

8

- (Hydroxymethyl)benzeneacetic acid (3-endo)-8-methyl-8- azabicyclo[3.2.1]oct-3-yl ester sulphate monohydrate

Atropine•Atropine is (+)-hyoscyamine ( 莨菪碱 ), an ester of the tropic acid and tropine.

•Vitali reaction for tropic acid

•Natural product is (-)-hyoscyamine.

•Antimuscarinic effect:

S(-)-Hyoscyamine > Atropine >> R(+)-Hyoscyamine

Atropine results from the base-catalyzed racemization of the chiral carbon of tropic acid, which occurs during isolation process. N

CH3

H

O

O

HOH

12

3456

7

8

Anisodanmine hydrobromide( 氢溴酸山莨菪碱 )

NH3C

H

O

O

HO

CH2OH

*

HBr

(S)- (Hydroxymethyl)benzeneacetic acid 6β-hydroxy-1αH, 5αH-8-methyl-8- azabicyclo[3.2.1]oct-3 α -yl ester hydrobromide

Synthetic Muscarinic antagonists

• Administered orally or by parenteral routes

• Therapeutic Use: Treatment of GI disorder (in combination with Librium ( 利眠宁 ), a tranquilizer)

• Contraindicated ( 禁忌 ) in glaucoma ( 青光眼 )

Amino Alcohol Ester of Synthetic Muscarinic antagonistsSynthetic Muscarinic antagonists

O

O ON

H3C CH3

CH3

CH3

CH3

Br

Propantheline Bromide (溴丙胺太林)

O

O

OH

N CH3

CH3

. HCl

Benactyzine Hydrochloride(盐酸贝那替秦)

O

O

OH

N CH3

CH3

. BrCH3

Benactyzine Methobromide （溴化甲基苯羟乙胺）

NCH3

O

O

OH

Br

Clidinium Bromide (氢溴酸环奎二苯酯)

O

ON

N

H3COH

. HCl

Oxyphencyclimine Hydrochloride (盐酸羟苄利明)

NCH3

O

O

OH

Br

H3C

Glycopyronium Bromide

O

ON

OH

CH3

CH3

CH3

Br

Oxyphenonium Bromide (氢溴酸奥芬铵)

Anticholinergic Amino Alcohols

OH

N

Procyclidine (丙环定)

OH

N HCl.

Trihexyphenidyl Hydrochloride (苯海索盐酸)

OH

N HCl.

Biperiden(比哌立登)

NCH3

O CH3SO3H.

Benztropine Mesylate(苯扎托品甲磺酸)

O

CH3

NCH3

CH3

. HOCCOOH

CH2COOH

CH2COOH

Orphenadrine Citrate(奥芬那君柠檬酸盐)

Anticholinergic Amino Ethers

Propantheline Bromide ( 溴丙胺太林 )

O

O ON

H3C CH3

CH3

CH3

CH3

Br

N-Methyl-N-(1-methylethyl)-N-[2-[(9H-xanthen(咕吨 )-9-ylcarbonyl)oxy]ethyl]-2-propanaminium bromide

•Potent peripheral antimuscarinic effect

•Weak Ganglionic ( 神经节的 ) blocking effect

• Selectivity for Gastrointestinal tract

•Treat or prevent spasm ( 痉挛 ) in the muscles of the gastrointestinal tract.

Actions and Uses

Recent Muscarinic Antagonists

Subtype selective muscarinic antagonists.

•M1-selective antagonist

•Clinical trials for the treatment of duodenal ulcers ( 十二指肠溃疡 )

N

HNO

S

N

N

O

CH3

CH3

N

HNO

N

N

O

CH3

Pirenzepine（哌仑西平）

Telenzepine（替仑西平）

Nicotinic Antagonists

Two subclasses:

• Ganglionic blocking agents ( 神经节传导阻滞剂 )

(N1-receptor antagonist)

• Skeletal neuromuscular blocking agents ( 骨骼肌神经肌肉阻滞药 ) (N2-receptor antagonist)

Skeletal Muscular Relaxants（骨骼肌松弛药）

• Central Muscular relaxants

• Skeletal neuromuscular blocking agents

(N2-receptor antagonist)

NH

O O

ClChlorzoxazone ( 氯唑沙宗 )

Neuromuscular Blocking Agents

Classification:• Nondepolarizing (Competitive Neuromuscular

Blocking Agents) : inactive on N2-receptor

• Depolarizing (Noncompetitive Neuromuscular Blocking Agents) : to activate N2-receptor

• 极化状态：神经和肌纤维在静止状态时，其膜内呈负电位，膜外呈正电位，称“极化状态”。

• 去极化：当正常神经冲动达到神经肌肉接头使神经末梢释放乙酰胆碱时，后者与运动板膜上的胆碱受体结合，促使膜对某些离子的通透性改变，使膜内外的电位差呈一时性消失，引起“去极化”，从而产生动作电位，导致肌肉收缩。

• 非去极化型：本型肌松药能竞争占膜上的胆碱受体，阻断乙酰胆碱的去极化，而其本身并不产生去极化作用，结果使骨骼肌松弛。可被抗胆碱酯酶药新斯的明所对抗。

• 去极化型：本型肌松药能与终板膜上的胆碱受体结合，产生去极化状态，且去极化状态较乙酰胆碱持久，导致终板对乙酰胆碱的反应性降低，因而也产生肌肉松弛。不被抗胆碱酯酶药新斯的明所对抗，而且加剧这种作用。

• 神经肌肉阻断剂：非去极化型和去极化型两大类。• － 非去极化型肌松药容易调控，比较安全，临床用

肌松药多为此类。• － 去极化型肌松药起效快，持续时间短，如氯琥珀

胆碱。• － 具有去极化和非去极化双重作用，如溴己氨胆碱

，起初发生短时间的去极化，接着产生较长时间的非去极化，适用于大手术。

Specific Depolarizing Neuromuscular Blocking Agents

Succinylcholine chloride ( 氯化琥珀酰胆碱 )

• Very short duration of action (iv)

• Rapid hydrolyzed and rendered inactive by plasma esterase.

• Use: Muscle relaxant. Suitable for short periods of relaxation. Suitable for continuous iv drip.

ON(CH3)3

ON(CH3)3

O

O

Cl

Cl

Specific Nondepolarizing Neuromuscular Blocking Agents

• d-Tubocurarine (筒箭毒碱 ) and Metocurine (甲筒箭毒 )

•Steroid Based Neuromuscular Blocking Agents

•Tetrahydroisoquinoline (四氢异喹啉 ) Based Neuromuscular Blocking Agents

d-Tubocurarine and Metocurine

d-Tubocurarine （筒箭毒碱）•Plant alkaloid. Isolated from Chondodendron tomentosum.南美防己属• Causes muscle paralysis (arrow poison).• only one quaternary ammonium group.• Administered intravenously and has a long duration of action. Primarily excreted as unchanged drug in the urine and bile. • Therapeutic Use: As a muscle relaxant in various surgical procedures.

Metocurine （甲筒箭毒碱）•A semi-synthetic analog of tubocurarine. •As a bis-quaternary ammonium compound, it is about four times more potent than the parent compound.

Tetrahydroisoquinoline Based Neuromuscular Blocking Agents

N

H3CO

H3CO

H3COOCH3

O O

O O

NOCH3

OCH3

OCH3

OCH3

CH3 H3CC6H5SO3

2

Atracurium besylate

Atracurium Besylate (苯磺阿曲库铵 )

•A nondepolarizing neuromuscular blocker

•The quaternary ammonium groups are located in two substituted tetrahydroisoquinoline rings separated by an aliphatic diester.(13 atoms)

•Duration of action is slightly longer than that of succinylcholine ( 琥珀酰胆碱 ).

•Metabolism:

Ester hydrolysis and Hoffmann elimination

•Metabolism:

Ester hydrolysis and Hoffmann elimination

N

H3CO

H3CO

H3CO

OCH3

O O

O O

NOCH3

OCH3

OCH3

OCH3

CH3 H3C

N

H3CO

H3CO

H3CO

OCH3

O O

O O

NOCH3

OCH3

OCH3

OCH3

CH3 H3C

Steroid Based Neuromuscular Blocking Agents

R1

R3OH

H

HCH3

CH3

H

R2

O

O

CH3

Pancuronium bromide泮库溴铵

R1=R2= N

H3C

2Br R3= CH3

O

Vecuronium bromide维库溴铵 R1= N N

H3C

Br

R2= R3= CH3

O

Pipecuroniumbromide哌库溴铵

NNCH3

CH32BrR1=R2= R3= CH3

O

Rocuroniumbromide罗库溴铵 R1= ON N

Br

R2= R3= CH3

O

O

H

O

N

O

N

H

H

H

O2Br-

1,1′-[(2,3,5 ,16 ,17 )-3,17-Bis(acetyloxy) androstane-2,16- diyl] bis[1-methyl piperidinium]dibromide

Pancuronium Bromide (泮库溴铵 )

Actions and Uses

•Long acting Nondepolarizing Neuromuscular Blocking agent

•More active than tubocurarine

•Increase heart rate and blood pressure and not be used in patients with coronary artery disease (冠脉疾病 ).

•Hydrolysis in the liver to the active 3-hydroxy metabolite and inactive 17-hydroxy and 3,17-dihydroxy metabolites.

Norepinephrine and Epinephrine (adrenal gland) are the postganglionic （节后纤维） neurotransmitters.

Stimulation of Sympathetic Nervous System （交感神经系统） :

• Increased rate and force of heart contractions

• Rise in blood pressure

• Shift of blood flow to skeletal muscles

• Dilation of bronchioles and pupils

• Increase in blood glucose levels (gluconeogenesis, 糖原异生 and glycogenolysis, 糖原分解 )

3.3 Adrenergic Drugs ( 拟肾上腺素药 )

•Belong to chemical class of substances known as the Catecholamines (儿茶酚胺 ).

•Polar compounds, containing both basic and acidic functional groups.

•Chiral compounds. Natural enantiomer has R-configuration.

•Undergoes oxidation in prolonged exposure to air.

•Limited therapeutic use.

Norepinephrine Epinephrine (Adrenaline)

Structures of Norepinephrine and Epinephrine

Adrenergic Receptors

•G-Protein coupled receptors (GPCR, G-蛋白偶联受体 ).•Initial classification into α and β receptor subclasses (Ahlquist, 1948).•Classification based on responses to different adrenergic receptor agonists, such as, Norepinephrine (NE), Epinephrine(EP), and Isoproterenol(ISO).α-receptor: α1, α2

β-receptor: β1, β2, β3:

•Agonism Potencyα1, α2: EPI ≥ NE >> ISOβ1: ISO > EPI = NE; β2: ISO > EPI >> NE; β3: ISO = NE > EPI

•Receptor LocalizationGenerally, α1, β1, β2 are postsynaptic receptors （突触后受体） ; α2 is a presynaptic receptor （突触前受体） .

Tissue Responses to Adrenoceptor Stimulation

Organ / Tissue Receptor ResponsesArterioles α1 Constriction小动脉 β2 DilationHeart β1 Increased rate and forceLungs β2 Relaxation (bronchial dilation)Liver α, β Increased glycogenolysis and GluconeogenesisFat cells α, β LipolysisIntestine α, β Decreased motilityKidney β1 Renin secretionVeins α Constriction β2 Dilation

Sympathomimetic Agents ( 拟交感神经药 )

•Direct Acting Drug (Adrenergic Agonists) √Interacts directly with the adrenergic receptors, eliciting （诱发） sympathomimetic response.•Indirect Acting Drug Causes release of Norepinephrine from the adrenergic nerve terminals.•Mixed Acting Drug √ Interacts directly with the adrenergic receptors and also causes release of Norepinephrine.

Direct Acting Sympathomimetic Agents (Adrenergic Agonists)

•Endogenous Catecholamines

•SAR of Adrenergic Agonist

•α-Adrenergic Receptor Agonists

-Adrenergic Receptor Agonists

Endogenous Catecholamines and Therapeutic Uses

Norepinephrine, Epinephrine and Dopamine are three naturally occurring catecholamines

Norepinephrine Epinephrine Dopamine

Chemical Property of Catecholamines

HO

HO

HN

OH

R [O]

H2O

O

O

HN

OH

R H2

NO

OHO

RNO

OHO

RNO

OHO

R n

Norepinephrine

•Potent stimulant of both α and β adrenoceptors•Limited therapeutic value•Used to maintain blood pressure in acute hypotensive states （低血压状态）•Substrate for MAO and COMT, not effective orally•Chiral compounds. Natural enantiomer has R-configuration. Racemization occurs in heat or acid condition.•Undergoes oxidation in prolonged exposure to air. Sodium bisulfite used as antioxidant in NE preparations

4-((R)- 1-hydroxy-2-amino- ethyl)- 1,2-benzenediol

Epinephrine

• Potent stimulant of both α and β adrenoceptors;• Drug of choice for reversal of acute hypersensitivity

reactions (anaphylaxis ，过敏反应 );• Enhances the action of local anesthetics (restricts local

blood flow);• Poor oral absorption. Rapidly metabolized by MAO and

COMT;• Degrades on exposure to air and light;• Serious side effects include cerebral hemorrhage (脑出血 ) and cardiac arrhythmias (心律不齐 ).

α-Adrenergic Receptor Agonists

α1−Selective Adrenergic Agonists:• Stimulation of vascular smooth muscle.• Maintenance of blood pressure in hypotension （低血压） or shock

Phenylephrine去氧肾上腺素

Methoxamine甲氧明

Metaraminol间羟胺

-Adrenergic Receptor AgonistsMost of the -selective adrenergic agonists are used primarily as bronchodilators （支气管扩张剂） in asthma （哮喘症） and other constrictive pulmonary conditions.

Isoprenaline （异丙肾上腺素）

•Highly potent bronchodilator•Non-selective (β1 and β2) and leads to cardiac stimulation caused by its β1-activity.•Metabolized primarily by COMT (Poor substrate for MAO)

2-Agonists (Phenylethanolamines)

•Primarily used as bronchodilators in the treatment of asthma•Selectivity (β1 vs. β2) is poor at high doses•Administration by inhalation (aerosol ，气雾剂 ) enhances β2-selectivity (pulmonary)

Specific agents:

Salbutamol （沙丁胺醇） , Salmeterol （沙美特罗）

Salbutamol (Albuterol)沙丁胺醇

HO

HO

HN CH3

OH

H3C CH31

2

2-[(1,1-Dimethylethyl)amino]-1-[4-hydroxy-3- (hydroxymethyl)phenyl]ethanol

•Selective β2 agonist•Orally active drugs, also available for inhalation therapy;•Not metabolized by MAO or COMT; •Bronchodilator used for the treatment of asthma, chronic bronchitis, and other breathing disorders

The Synthesis of Salbutamol

HO

COCH3HCHO, HCl

HO

COCH3Cl Ac2O

COCH3

Br2

N

O

H3C CH3CH3

PhCH2NHC(CH3)3

OH3C

O

O

OH3C

COCH2BrOH3C

O

O

OH3C

OH3C

O

O

OH3C

HCl, H2O

HO

HON

O

H3C CH3CH3

(1) H2, Pd C

(2) H2SO4

HO

HO

HN CH3

OH

H3C CH3

Metabolism of Salbutamol

OH

HO

HN CH3

OH

H3C CH3

OH

O

HN CH3

OH

H3C CH3

SOO

OH

4-O-Sulfate Salbutamol

OH

O

HN CH3

OH

H3C CH3

O

OH

OH

OH

HO

4-O-Glucuronide

Salmeterol （沙美特罗）

HO

HO

OHHN

O

•Long lipophilic substituent•Prolonged duration of action (~ 12 hrs)•Slow onset (not suitable alone for prompt relief of bronchospasm ，支气管痉挛 )

1-Adrenergic Agonists

HO

HO

NH2 HO

HO

HN

CH3

OH

Dopamine Dobutamine

（多巴酚丁胺）

•Not strictly an adrenergic drug, acts on dopamine receptors.•Stimulates cardiac 1-AR through both direct and indirect mechanisms. •Used to correct hemodynamic （血液动力学的） imbalances induced by shock, trauma （外伤） , or congestive heart failure （充血性心力衰竭） .•Rapidly metabolized by MAO and COMT. Not effective orally.

Dopamine

Sympathomimetics （拟效感神经药） with Mixed Mechanism of Action

HN

CH3

OH

CH3

HCl

Ephedrine Hydrochloride （盐酸麻黄碱）

(1R,2S)-2-methylamino-1-phenylpropan-1-ol hydrochloride

HN

CH3

OH

CH3

HN

CH3

OH

HO

HO

① not be affected by COMT, prolonged durationDecreased molecular polarity, easily enter CNS, cause stimulation. ② ： -methyl group, not be easily affected by MAO. prolonged duration, decreased molecular polarity, increased CNS toxicity.

Actions and Uses

Ephedrine Hydrochloride

C

C

CH3

H OH

H NHCH3 C

CH3

HHO

HH3CHN

C

C

CH3

HO H

H NHCH3 C

CH3

OHH

HH3CHN

•Natural product, isolated from various species of Ephedra.•Long history of use in traditional Chinese medicine (Ma Huang)•Four isomers of Ephedrine

(-)-Ephedrine (+)-Ephedrine (+)-Pseudoephedrine (-)-Pseudoephedrine

(+)-Pseudoephedrine (伪麻黄碱 )

• An alkaloid. A diastereoisomer ( 非对映异构体） of ephedrine,

• Used as a nasal decongestant （减充血剂） (many OTC preparations available)• To be used with caution in hypertensive individuals

Enantiomer： 对映体

Structure Activity Relationship (SAR) of Adrenergic Agonist

HN

R2

R1

OH

R3

12

3

4

56

The parent structure of the sympathomimetic amines is β-phenylethanolamine

Phenylethanolamine Adrenergic Agonists

3.4 Histamine H1 Receptor Antagonists

•Histamine and Allergy

•Development and the Structures of H1-receptor Antagonists

•SAR of H1-Receptor Antagonist

•Specific Agents

Histamine and Allergy

HN N

NH2

•Histamine is widely existed in many tissues

•Complex physiological functions

• One of mediators involved in allergic response (H1)

•Important in the regulation of the secretion of gastric acid (H2)

2-(imidazol-4-yl)ethylamine

Histamine

N NH

NH2

Therapeutic Options in Management of Allergic Reaction

① Antihistamines （抗阻胺药）② Decongestants （减充血剂）③ Anticholinergics （抗胆碱药）④ Corticosteroids （皮质甾醇类）⑤ Mast cell stabilizers （肥大细胞稳定剂） ⑥ Leukotriene receptor antagonists （白三烯受体拮抗剂）

⑦ Immunotherapy （免疫治疗）

Antihistamines Background

•Antihistamine is a drug which serves to reduce or eliminate effects mediated by histamine.

•In common use, the term antihistamine refers only to H1-receptor antagonists, also known as H1-antihistamines.

•The first H1-antihistamine discovered was piperoxan (哌罗克生 ), by Forneau and Daniel Bovet (1933). Bovet won the 1957 Nobel Prize in Physiology or Medicine for his contribution.

Side Effect of H1 Antihistamines

•Other adverse effects in first-generation H1-antihistamines include:

dizziness ( 头晕 ), blurred vision ( 视物模糊 ), anxiety ( 视物模糊 ), nausea and vomiting (恶心和呕吐 ), constipation ( 便秘 ), diarrhoea ( 腹泻 ), dry mouth (口干 ), and dry cough (干咳 )

•The most common adverse effect is sedation - this "side effect" being utilized in many OTC sleeping-aid preparations.

Chemical classifications of H1 Antihistamines

•Alkylamines•Aminoethers•Ethylenediamines•Tricyclics•Piperazines•Piperidines

Antihistamines (Alkylamines)

NCH3

CH3

Cl

N

Chlorphenamine（氯苯那敏）

Cl

N

N

H

N

H3C N

H

N

H3C

COOH

Pyrrobutamine （吡咯他敏）

Triprolidine （曲普利啶） Acrivastine （阿伐斯汀）

N NH

NH2

Antihistamines (Aminoethers)

R R1 R2

Medrylamine 甲氧拉敏

OCH3

H

Chlorodiphenhydramine Cl

H

Bromodiphenhydramine 溴苯海拉明

Br

H

Carbinoxamine 卡比沙明

Cl N

H

Doxylamine 多西拉敏

H N

CH3

ON

CH3

CH3R1

R2

R

ON

CH3

CH3HCl

Diphenhydramine Hydrochloride

盐酸苯海拉明

Cl

ON

Clemastine

氯马斯汀

Ethylenediamines

R

NR1

NCH3

CH3

R R1

Phenbezamine 芬苯扎胺

Mepyrarnime 美吡拉敏 N

O

Tripelennamine 曲吡那敏 N

Methaphenilene 美沙芬林

S

Methapyrilene

美沙吡林 N S

Thenyldiamine

西尼二胺 N

S

Promethazine HCl盐酸异丙嗪

Tricyclics

N

CH3

HCl H2O32

Cyproheptadine Hydrochloride

盐酸赛庚啶S

N

CH3

O

HHOOC

H COOH

Ketotifen Fumarate

富马酸酮替芬 Loratadine氯雷他定

N

N

Cl

OO

Piperazines

R1

NN

R2Cl

NN

O COOH

2HCl*

Cetirizine Hydrochloride盐酸西替利嗪

R1 R2

Decloxizine 去氯羟嗪

H CH2CH2OCH2CH2OH

Cyclizine 赛克力嗪

H CH3

Chlorcyclizine 氯环利嗪

Cl CH3

Meclizine 美克洛嗪

Cl H2C

CH3

Buclizine 布克力嗪

Cl CH2 C(CH3)3

Piperadines

N

N

F

NOCH3

NHN

N

F

NN

HN

N

O

CH3NN

O

Cl

N CH3

Astemizole （阿司咪唑） Mizolastine （咪唑斯汀） Azelastine （氮卓斯汀）

HO

N

OH

CH3

R

CH3

Terfenadine （特非那定）, R=CH3,Fexofenadine （非索非那定）, R=COOH

N

CH3

R

CH3

Ebastine （依巴斯汀）, R=CH3Carebastine （卡瑞斯汀）, R=COOH

OO

Specific Agents

• Chlorphenamine Maleate （马来酸氯苯那敏）• loratadine （氯雷他定）• Cetirizine Hydrochloride （盐酸西替利嗪）• Mizolastine （咪唑斯汀）

Chlorphenamine Maleate (马来酸氯苯那敏 )

-（ 4-Chlorophenyl） -N,N-dimethyl-2-pyridinepropanamine maleate (1:1)

COOH

COOH

NCH3

CH3

Cl

N

*

•(S)-(+)-isomer > () > > ( R )- (-)-isomer

Action and Use

•First generation of H1 Antihistamines: The most common side effect of these agents is CNS depression including sedation, drowsiness etc.

•Prevent the symptoms of allergic conditions such as rhinitis （鼻炎） and urticaria （荨麻疹） .

Loratadine ( 氯雷他定 )

4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine-11-ylidene)-piperidine carboxylic acid ethyl ester

N

N

Cl

OO

1 2

34

14

56

8 11

Metabolism

desloratadine

N

NH

Cl

Metabolite : desloratadine is potent antagonism of hismtamine H1 Receptor.

It was launched as new drug in 2001.

• Second generation of antihistamine: also called second generation nonsedating H1 antihistamines.

• Potent effect, prolonged action, etc.• No antiadrenergic and anticholinergic effects, no CNS

depression.• Relieves symptoms of allergic rhinitis, such as, itchy

(痒 ), sneezing (喷嚏 ); and runny nose.

Action and Use

Cetirizine Hydrochloride (盐酸西替利嗪 )

Cl

NN

O COOH

2HCl*

()-2-[2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl]ethoxy]acetic acid dihydrochloride

Action and Use

Second Generation Antihistamines:• Little antiadrenergic and anticholinergic effects• No CNS depression• No reported cardiac side effect• Effective against rash/hives ( 皮疹 /荨麻疹 )

Mizolastine (咪唑斯汀 )

N

N

F

NN

HN

N

O

CH3

2-[[1-[1-[(4-Fluorophenyl)methyl]-1H-benzimidazol-2-yl-4-piperidinyl]methylamino]-4(1H)-pyrimidinone

Action and Use

1. Second Generation Antihistamine• Have both antihistamine and inhibition of

mediators of inflammation, and no reported cardiac side effect, better than other second generation antihistamines.

• Fast onset, potent and prolonged effects.2. The principal metabolic pathway is glucuronidation

of the parent compound. 3. Relief of seasonal allergic rhinitis and urticaria.

Ar1 X C NR

R1

benzene,heterocycle,substituted aromaticring or tricycle

Basic strucutre

n=2~3

tertiary amine, piperidine,or piperazidine

n

Ar

sp2 or sp3 hybridized C, N, O

Structural features

Features of three generation antihistamines• The first genetation antihistamines have effects at

cholinergic, adrenergic, dopaminergic and serotonergic receptors. The most common side effect of these agents is CNS depression including sedation, drowsiness, etc.

• The second generation antihistamines have improved H1 receptor selectivity, little or no sedative qualities, and the antihistamines have been called second genetation nonsedating H1 antihistamines (e.g., loratadine, cetirizine, mizolastine).

• The third generation antihistaminics (e.g., desloratadine) have high H1 receptor selectivity, no sedative qualities and no cardiac toxicity.

3.5 Local Anesthetics

• Development of Local Anesthetics• Structures of Local Anesthetics• Mechanism of action• Structure-activity Relationships• Specific Agents

A local anesthetic agents is a drug that, when given either topically or parenterally to a localized area, produces a state of local anesthesia by reversibly blocking the nerve conductances that transmit the feeling of pain from this locus to the brain.

Development of Local Anesthetics

CH3 CH3

O

O

OON

Cocaine (1860, 1884 use)可卡因

CH3

OH

OOHN

Ecgonine (No activity)爱康宁

COOH CH3OH+ +

CH3

O

N

O

Tropacocaine托派可卡因(Local anesthetic activity)

OCH3

O

O

ONHO

ONH

alpha-Eucaine优卡因 beta-Eucaine

(activity)

•The benzoate is important for the anesthetic activity

O

H2N

CH3O

Benzocaine (1890)苯佐卡因

CH3

CH3O

H2N

NO

Procaine (1904)

Structures of Local Anesthetics

•Amino Esters

•Amino Amides

•Amino Ethers

•Amino Ketones

Amino Esters

CH3

CH3

C4H9

O

HN

NO

Tetracaine丁卡因

O

NHC3H7O

Meprylcaine美普卡因

C2H5

C2H5

O

H2N

NO

Butacaine布他卡因

CH3

CH3O

H2N

NO

Procaine

CH3

CH3O

H2N

NO

R

R=Cl Chloroprocaine

R=OH Hydroxyprocaine

O

H2N

CH3O

Benzocaine

Amino Amides

CH3

CH3

HN

NC

OR

R=CH3, Mepivacaine，甲哌卡因R=C4H9, Bupivacaine，布比卡因

CH3

CH3

NHCCHN

O

C2H5

C2H5

C3H7

Etidocaine，依替卡因

C2H5

C2H5

NO

CH3

CH3 HN

Lidocaine利多卡因

CH3NH

O

HN

CH3 CH3

Prilocaine丙胺卡因

Amino Ethers

CH3

CH3

NO

N

H3C

H3C O

OO

N

Dimethisoquin二甲异喹

Pramocaine普莫卡因

Amino Ketones

H3C O

O

NH3C

O

O

N

Dyclonine达克罗宁

Falicaine

Action of Mechanism

Action of Mechanism (cont)

SAR of Local Anesthetics

R1

Y

Z Nn

R2

R3

Lipophilic portion Intermediate chain Hydrophilic portion

>NH

>S

>O

electrondonating groupsubstituted in ortho andpara position willincrease the activity;electronwithdrawinggroup substituted willlower the activity

secondary amine, tertiaryamine, piperidine,pyrrolidine, morpholinepKa value: 7.5-9.0

n= 2 or 3

SAR of Local Anesthetics (cont)

R1

Y

Z NnR2

R3

Lipophilic portion Intermediate chain Hydrophilic portion

n= 2 or 3

Stability: C O

O< C S

O< C NH

O< C CH2-

O

Potency: C S

O> C O

O> C CH2-

OC NH

O>

Y=-CH2-, -O-, lower the activityY=-CH=CH- (conjugated function group), keep the activity

Procaine Hydrochloride (盐酸普鲁卡因 )

CH3

CH3O

H2N

NO

HCl

4-Aminobenzoic acid-2-(diethylamino)ethyl ester Hydrochloride

•Procaine hydrochloride is a local anesthetic used primarily in dentistry.

•Procaine was first synthesized in 1904, and was the first injectable man-made local anesthetic used in clinic.

•Procaine is an ester anesthetic and is metabolized in the plasma by the enzyme pseudocholinesterase ( 拟胆碱酯酶 ) through hydrolysis into para-aminobenzoic acid (PABA), which is then excreted by the kidneys into the urine.

Action and Use

The Synthesis of Procaine Hydrochloride

CH3

CH3

H2N

NO

CH3

CH3O

O2N

NO

CH3

CH3

NHONa2Cr2O7

HClFe+HCl

NO2

CH3O OH

NO2

CH3

CH3

H2N

NO

HCl

H2SO4

OO

xylene

Lidocaine Hydrochloride (盐酸利多卡因 )

C2H5

C2H5

NO

CH3

CH3

HCl H2ON

H

2-（ Diethylamino） -N-（ 2,6-dimethylphenyl） acetamide hydrochloride monohydrate

• Faster acting and longer lasting than procaine

• popular local anesthetic often used in dentistry or topically

• used in the treatment of ventricular cardiac arrhythmias (室性心律不齐 ) and cardiac arrest （心跳骤停） .

• metabolized in the liver and excreted by the kidneys.

Action and Use

Dyclonine Hydrochloride (盐酸达克罗宁 )

H3C O

O

N HCl

1-(4-Butoxyphenyl)-3-(1-piperidinyl)-1-propanone hydrochloride

Action and Use

• Not administered by injection because of its tissue-irritating property

• Usually used as topical anesthetic

Emphasis• 1. Master structures of Bethanechol Chloride,

Neostigmine Bromide, Atropine Sulfate, Epinephrine, Salbutamol, Ephedrine Hydrochloride, Chlorphenamine Maleate, Cetirizine Hydrochloride, Procaine Hydrochloride .

• 2. Know structures of Propantheline Bromide, Pancuronium Bromide, Atracurium Besylate, Norepinephrine, Salmeterol, Loratadine, Mizolastine, Lidocaine Hydrochloride, Dyclonine Hydrochloride.

• 3. Know SARs of Cholinergic agonists, Adrenergic Agonist, Local Anesthetics,

• 4. Know targets of all kinds of drugs.

• 5. Know chemical classifications of H1 Antihistamines, Local Anesthetics.

• 6. Know Features of three generation antihistamines• 7. Know local anesthetic’s action of mechanism.• 8. Know synthetic route of Bethanechol Chloride,

Salbutamol, Procaine Hydrochloride.