Transcript Chapter 3 Peripheral nervous system drugs

Medicinal Chemistry
Chapter 3
Peripheral Nervous System Drugs
Outline
Drug Affecting Cholinergic
Neurotransmission
Drug Affecting Adrenergic
Neurotransmission
Antihistamines
Local Anesthetics
Cholinergic Drugs
Anticholinergic Drugs
Adrenergic Drugs (agonist)
Adrenergic Antagonist (Chapter 4)
Histamine H1 Receptor Antagonists
3.1 Cholinergic Drugs （拟胆碱药）
• Cholinergic effect
Mediated by acetylcholine （ACh）
Biosynthesis of Acetylcholine
The Classification of Cholinergic Drugs
Cholinocepter agonists
Cholinergic Drugs
Acetylcholinesterase inhibitors
(AChEIs)
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)
Cholinocepter agonists
SAR of Cholinocepter agonists
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.
Bethanechol Chloride （氯贝胆碱）
2-[(Aminocarbonyl)oxy]-N,N,N-trimethyl-1-propanaminium chloride
CH3
H
N
H
O
NH2
>
O
(S)-Bethanechol Chloride
240 fold
N
H 3C
O
NH2
O
(R)-Bethanechol Chloride
Actions and Uses
• Potent muscarinic agonist. Orally effective,
administered by subcutaneous (皮下) injection.
also
• 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
Synthesis:
Future Muscarinic Agonists
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)
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
• Indirect acting cholinergic agonists
• 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.
Reversible AChEIs
• Classical AChEIs
• Nonclassical AChEIs
NH2
CH 3
CH3O
CH 2
N
Tacrine
他克林
N CH2
CH3O
O
HCl
Donepezil (Aricept)
多奈哌齐
H 3C
N
CH3
CH 3
O
N
CH 3
O
Rivastigmine (Exelon)
卡巴拉汀
Neostigmine Bromide （溴新斯的明）
3-[[[(Dimethylamino)carbonyl]oxy]-N,N,Ntrimethylbenzenaminium 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）
•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 hepatotoxicity
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）
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
- (Hydroxymethyl)benzeneacetic acid (3-endo)-8-methyl8- 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.
Atropine results from the base-catalyzed racemization
of the chiral carbon of tropic acid, which occurs during
isolation process.
•Antimuscarinic effect:
S(-)-Hyoscyamine > Atropine >> R(+)-Hyoscyamine
Anisodanmine hydrobromide
(氢溴酸山莨菪碱)
H3 C
N
HO
HBr
H
CH2 OH
O
O
*
(S)- (Hydroxymethyl)benzeneacetic acid 6βhydroxy-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 antagonists
Anticholinergic Amino Alcohols
Anticholinergic Amino Ethers
Propantheline Bromide (溴丙胺太林)
N-Methyl-N-(1-methylethyl)-N-[2-[(9H-xanthen(咕
吨)-9-ylcarbonyl)oxy]ethyl]-2-propanaminium
bromide
Actions and Uses
•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.
Recent Muscarinic Antagonists
Subtype selective muscarinic antagonists.
•M1-selective antagonist
•Clinical trials for the
treatment of duodenal ulcers
(十二指肠溃疡)
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
Chlorzoxazone (氯唑沙宗)
• Skeletal neuromuscular blocking agents
(N2-receptor antagonist)
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.
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
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
H3 CO
O
N
CH3
H3 CO
O
O
OCH3
O
N
OCH3
H3C
H3CO
OCH3
OCH 3
H3CO
OCH3
O
N
CH3
H3CO
H3CO
OCH3
O
O
O
OCH 3
N
H 3C
OCH 3
OCH 3
OCH3
Steroid Based Neuromuscular Blocking Agents
Pancuronium Bromide (泮库溴铵)
O
O
N
H
N
H
O
H
2Br-
H
O
1,1′-[(2,3,5 ,16 ,17 )-3,17-Bis(acetyloxy) androstane2,16- diyl] bis[1-methyl piperidinium]dibromide
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.
3.3 Adrenergic Drugs (拟肾上腺素药)
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)
Structures of Norepinephrine and Epinephrine
Norepinephrine
Epinephrine (Adrenaline)
•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.
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 Potency
α1, α2: EPI ≥ NE >> ISO
β1: ISO > EPI = NE;
β2: ISO > EPI >> NE;
β3: ISO = NE > EPI
•Receptor Localization
Generally, 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
Arterioles
小动脉
Heart
Lungs
Liver
Fat cells
Intestine
Kidney
Veins
Receptor
α1
β2
β1
β2
α, β
α, β
α, β
β1
α
β2
Responses
Constriction
Dilation
Increased rate and force
Relaxation (bronchial dilation)
Increased glycogenolysis and
Gluconeogenesis
Lipolysis
Decreased motility
Renin secretion
Constriction
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
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
4-((R)- 1-hydroxy-2-amino- •Chiral compounds. Natural enantiomer
ethyl)- 1,2-benzenediol
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
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 Agonists
Most 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 β1activity.
•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
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
Metabolism of Salbutamol
Salmeterol （沙美特罗）
•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
Dopamine
Dobutamine
（多巴酚丁胺）
Dopamine
•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.
Sympathomimetics （拟效感神经药） with
Mixed Mechanism of Action
Ephedrine Hydrochloride （盐酸麻黄碱）
(1R,2S)-2-methylamino-1-phenylpropan-1-ol
hydrochloride
Actions and Uses
① not be affected by COMT, prolonged duration
Decreased molecular polarity, easily enter CNS, cause
stimulation.
② ：-methyl group, not be easily affected by MAO.
prolonged duration, decreased molecular polarity,
increased CNS toxicity.
Ephedrine Hydrochloride
•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
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
Histamine
•Histamine is widely existed in many
tissues
•Complex physiological functions NH
2
N
HN
• One of mediators involved in
allergic
response (H1)
•Important in the regulation of the
secretion of gastric acid (H2)
2-(imidazol-4-yl)ethylamine
Therapeutic Options
in Management of Allergic Reaction
①
②
③
④
⑤
⑥
Antihistamines （抗阻胺药）
Decongestants （减充血剂）
Anticholinergics （抗胆碱药）
Corticosteroids （皮质甾醇类）
Mast cell stabilizers （肥大细胞稳定剂）
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 H1antihistamines.
•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
•The most common adverse effect is sedation this "side effect" being utilized in many OTC
sleeping-aid preparations.
•Other adverse effects in first-generation H1antihistamines 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)
Chemical classifications
of H1 Antihistamines
•Alkylamines
•Aminoethers
•Ethylenediamines
•Tricyclics
•Piperazines
•Piperidines
Antihistamines (Alkylamines)
Antihistamines (Aminoethers)
R
CH3
O
R1
N
CH3
O
N
CH3
HCl
CH3
R2
Diphenhydramine Hydrochloride
Medrylamine
R
OCH3
R1
盐酸苯海拉明
R2
H
甲氧拉敏
Chlorodiphenhydramine
Cl
H
Bromodiphenhydramine
Br
H
Cl
溴苯海拉明
Carbinoxamine
Cl
Doxylamine
多西拉敏
H
N
卡比沙明
H
N
O
CH3
N
Clemastine
氯马斯汀
Ethylenediamines
R
CH3
N
N
CH3
R1
R
R1
Phenbezamine
芬苯扎胺
Mepyrarnime
美吡拉敏
N
O
Tripelennamine
曲吡那敏
N
S
Methaphenilene
美沙芬林
S
Methapyrilene
美沙吡林
N
S
Thenyldiamine
西尼二胺
N
Tricyclics
HCl
N
Promethazine HCl
盐酸异丙嗪
3 H O
2
2
CH3
Cyproheptadine Hydrochloride
O
盐酸赛庚啶
S
HOOC
N
H
H
COOH
CH3
Ketotifen Fumarate
富马酸酮替芬
Loratadine
氯雷他定
Piperazines
Cl
N
O
R2
R1
COOH
N
N
*
N
2HCl
Cetirizine Hydrochloride
盐酸西替利嗪
Decloxizine
R1
R2
H CH2CH2OCH2CH2OH
去氯羟嗪
Cyclizine
H
CH3
Cl
CH3
赛克力嗪
Chlorcyclizine
氯环利嗪
Meclizine
美克洛嗪
Buclizine
布克力嗪
CH3
Cl
H2C
Cl
CH2
C(CH3)3
Piperadines
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)
•(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[1,2b]pyridine-11-ylidene)-piperidine carboxylic acid ethyl
ester
Metabolism
Metabolite : desloratadine is potent antagonism of
hismtamine H1 Receptor.
It was launched as new drug in 2001.
desloratadine
Action and Use
• 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.
Cetirizine Hydrochloride (盐酸西替利嗪)
()-2-[2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin1-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)
2-[[1-[1-[(4-Fluorophenyl)methyl]-1H-benzimidazol2-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.
Structural features
Basic strucutre
benzene,
heterocycle,
substituted aromatic
ring or tricycle
Ar
Ar1
X
sp2 or sp3 hybridized C, N, O
C
tertiary amine, piperidine,
or piperazidine
N
n
R
R1
n=2~3
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
CH3 O
O
N
N
O
OH
OH
+
COOH + CH 3OH
O
Cocaine (1860, 1884 use)
可卡因
Ecgonine (No activity)
爱康宁
N CH3
O
O
O
NH
O
O
O
NH
O
CH3
alpha-Eucaine 优卡因
(activity)
O
beta-Eucaine
Tropacocaine 托派可卡因
(Local anesthetic activity)
•The benzoate is important for the anesthetic activity
Structures of Local Anesthetics
•Amino Esters
•Amino Amides
•Amino Ethers
•Amino Ketones
Amino Esters
Amino Amides
Amino Ethers
Amino Ketones
Action of Mechanism
Action of Mechanism (cont)
SAR of Local Anesthetics
Lipophilic portion
>
N
H
>
Intermediate chain
>
S
Hydrophilic portion
n= 2 or 3
O
Y
R3
Z
R1
electrondonating group
substituted in ortho and
will
position
para
increase the activity;
electronwithdrawing
group substituted will
lower the activity
n
N
R2
secondary amine, tertiary
amine, piperidine,
pyrrolidine, morpholine
pKa value: 7.5-9.0
SAR of Local Anesthetics (cont)
Lipophilic portion
Intermediate chain
Hydrophilic portion
Y
Z
n
N
R3
R2
R1
n= 2 or 3
Y=-CH2-, -O-, lower the activity
Y=-CH=CH- (conjugated function
group), keep the activity
Stability:
Potency:
O
C O <
O
C S >
O
O
C S < C NH <
O
C O >
O
C CH2-
O
C CH2->
O
C NH
Procaine Hydrochloride (盐酸普鲁卡因)
4-Aminobenzoic acid-2-(diethylamino)ethyl ester
Hydrochloride
Action and Use
•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.
The Synthesis of Procaine Hydrochloride
Lidocaine Hydrochloride (盐酸利多卡因)
2-（Diethylamino）-N-（2,6-dimethylphenyl）
acetamide hydrochloride monohydrate
Action and Use
• 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.
Dyclonine Hydrochloride (盐酸达克罗宁)
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.