AnticholinergicsAnticholinergics

PS postganglionicGanglionic & Neuromuscular blocking

agents

Cholinergic blocking agents Muscarinic & Nicotinic antagonists Muscarinic – Para sympatholytics Nic – N2 ganglionic blockers -

hexamethonium N1 - neuromuscular jn blockers eg

tubocurarine Atropine & related compounds

Atropa belladona, A. accuminata, Datura Strammonium, synthetic & semisyn compounds

MECHANISM OF ACTION 

Reduces the no. of free receptors that can interact with Ach.

The cholinergic blocking agents competitively inhibit the cholinergic receptors and prevent the binding of acetyl choline to the receptors due to the size of acyl group through ‘umbrella effect’.

The large group (alkyl or aryl) present in cholinergic blocking agents increase the affinity of the blocking agent and also block the approach of acetyl choline to the receptor.

Cholinergic Antagonists (Muscarinic receptor)Cholinergic Antagonists (Muscarinic receptor)

• Drugs which bind to cholinergic receptor but do not activate itDrugs which bind to cholinergic receptor but do not activate it• Prevent acetylcholine from bindingPrevent acetylcholine from binding• Opposite clinical effect to agonists - lower activity of Opposite clinical effect to agonists - lower activity of

acetylcholineacetylcholine

Postsynapticnerve

Ach

Antagonist

Ach

Postsynapticnerve

Ach

CLASSIFICATION 

1. Solanaceous alkaloids and Analogues - Atropine Sulfate, Hyoscyamine sulfate, Scopalamine HBr, Homatropine HBr, Ipratropium bromide. 

2. Amino alcohol esters - Cyclopentolate. HCl, Clidinium bromide, Dicyclomine HCl, Glycopyrrolate, Methanthelin bromide, Propanthelin bromide, Mepenzolate. 

3. Amino Alcohols- Biperidine HCl, Procyclidine HCl .

4. Amino alcohol ethers Benztropine mesylate, Orphenadrine 

5. Amino amides - Tropicamide, Isopropamide iodide. 6. Diamides – Ethopropazine HCl, Diethazine 7. Papaveraceous – Papaverine alkaloids 8. Miscellaneous - Pirenzepine, methixine HCl 

SAR

A quarternary ammonium function / tertiary amines protonated in biophase to form cationic species

N is separated from pivotal C by a chain- ester, ether or hydrocarbon moiety

A & B contain atleast 1 aromatic moiety for vander waals interaction, & 1 cycloaliphatic /hydrocarbon moiety for hydrophobic bonding interactions

C – may be hydroxyl or carboxamide – hydrogen bonding or can be component of A & B ring system, more potent if hydroxyl or hydroxymethyl

C

A

.B .CHAIN

.C

.N

A,B = Bulk groups, e.g., cycloalkyl,aromatic

C = H, OH, carboxamide

Alkyl substitution in N usually methyl, ethyl, propyl, isopropyl. The nitrogen in tertiary atom should contain alkyl group not larger than butyl for effective antagonist activity.

Groups A & B should be hydrophobic in nature

Distance b/w ring sub C & N – not critical may be 2-4 carbons

Most potent with 2 methylene units.

Highly potent antimuscarinic agents have ester grp (but not necessary for activity). The acyl group is always larger than acyl group in acetyl choline for good activity.

Hydrophobic substituents increase the affinity to binding the receptors and have good antagonist property.

C -The presence of free hydroxyl or carbamide is also important for hydrogen bonding with receptor.

Naturally occurring l-hyocyamine is more active than d-isomer.

Parasympathetic postganglionic Blocking

agents Competetive antagonism of Ach binding to

muscarinic receptors Potent agents – derived from muscarinic

agonists - one or two bulky grps Additional binding interaction - high affinity –

low intrinsic activity

Therapeutic effects Mydriatic effect

Dialation of pupil of the eye, cycloplegia, Antispasmodic effect

Lowered tone, motility of GI tract, genitourinary tract

Antisecretory effect Reduced salivation, perspiration, acid & gastric

secretions – used as preanaesthetic medicationSide effects: mydriasis, dryness of mouth, urinary

retentionUsed in treatment of Parkinson’s disease

Cvs PS tachycardia Heart sym vasodilation Arterioles sym dilation

Eye PS Mydriasis

GI tract PS Relaxation

Urinary B PS Urinary retention

Salivary G PS Dry mouth

Sweat G sym anhidrosis

Cholinergic Antagonists (Muscarinic receptor)Cholinergic Antagonists (Muscarinic receptor)

Clinical EffectsClinical Effects• Decrease of saliva and gastric secretionsDecrease of saliva and gastric secretions• Relaxation of smooth muscle Relaxation of smooth muscle • Decrease in motility of GIT and urinary tractDecrease in motility of GIT and urinary tract• Dilation of pupilsDilation of pupils

UsesUses• Shutting down digestion for surgeryShutting down digestion for surgery• Ophthalmic examinationsOphthalmic examinations• Relief of peptic ulcersRelief of peptic ulcers• Treatment of Parkinson’s DiseaseTreatment of Parkinson’s Disease• Anticholinesterase poisoningAnticholinesterase poisoning• Motion sicknessMotion sickness

Solanaceous Plants

Solanaceous alkaloids and analogs

Also known as the Deadly Nightshade Family. Hyoscyamus niger Atropa belladonna. Datura stramonium Have been used as poisons and hallucinogens (witches

and sorcerers)

Solanaceous alkaloids & analogues SAR

Chemistry Esters of bicyclic aminoalcohol 3-hydroxytropane Piperidine ring system in stable chair confirmation Isomers exist due to rigidity imparted to the molecule by

ethylene chain across 1,5 positions

NCH3

OH

H

TROPINE

Greater molar potency of atropine – blocks several moles of ACh

Umbrella-like artopine molecule inactivates adjacent receptors mechanically or electrostatically – unavailable

Amine grp seperated frm ester O by more than 2 C, but conformation by tropanal rings orients the molecule in a way that the distance is similar to Ach.

Most potent compounds – 2 lipophilic ring substitutions on C alpha to carbonyl of ester grp for mus activity

Comparison of atropine with acetylcholine

• Relative positions of ester and nitrogen similar in both molecules

• Nitrogen in atropine is ionised• Amine and ester are important binding groups (ionic +

H-bonds)• Aromatic ring of atropine is an extra binding group

(vdW) • Atropine binds with a different induced fit - no

activation

Atropine binds more strongly than acetylcholine Fully Fully ionised ionised

analogues unable to cross the blood brain barrier No CNS side effectsanalogues unable to cross the blood brain barrier No CNS side effects

N

OC

O

Me

H

CH

CH2OH

C

O

O CH3

NMe3

CH2CH2

Atropine USP

8-methyl-8-aza-bicyclo[3.2.1]octan-3-yl-3-hydroxy-2-phenyl propanoate Tropine ester of racemic tropic acid –optically inactive,

white odourless crystals bitter taste Piperidine ring in chair conformation Racemic form of hyoscyamine Racemic form of hyoscyamine Source - roots of belladonna (1831) (deadly nightshade)Source - roots of belladonna (1831) (deadly nightshade) Used as a poisonUsed as a poison Used as a medicine Used as a medicine

decreases GIT motility decreases GIT motility antidote for anticholinesterase antidote for anticholinesterase

poisoningpoisoning dilation of eye pupilsdilation of eye pupils CNS side effects – hallucinationsCNS side effects – hallucinations

• Opthalmic use of atropine a as mydriatic (dilating) agent has been largely replaced by use of analogs tropicamide and cyclopenatolate

•Also these antagonists can be used to treat the symptoms of an excess of acetylcholine, - exposure to an inhibitor of the enzyme acetylcholinesterase (such as a nerve gas).

•Atropine serves as an antagonist of acetycholine at the M2 receptor of the sinoatrial node.

•Used to treat some arrhythmias. (↑ ses HR by blocking effect of ACh on vagus.

Atropine is also used to avoid bradycardia (too slow heart rate) during some surgical procedures.

•

Hyoscyamine USP

Levorotatory form of racemic mixture atropine, obtained from solanaceous sp. (egyptian henbane)

Dextro form does not exist naturally Uses: Disorders of urinary tract, treat

spasms of bladder, as an antispasmodic

Scopolamine

Scopine ester found in H. Niger, Duboisia Myoporoides, Datura metel etc)

Levo component of racemic mixture atroscine, β- oriented epoxy grp bridged across 6,7

positions Uses: Effective in prevention of morning

sickness, (action on vestibular apparatus & cortex, depressant action)

Atropine stimulates CNS. Given as hydrobromide, transdermal systems

N

O

CH3

OH

H

SCOPINE

Papaverine alkaloids

Papaverine- Benzylisoquinoline alkaloids From opium poppy Muscarinic blocking action- spasmolytic on SM cardiac,

vascular and other SM- non specific antagonist used as antispasmodic for GIT spasms and in bronchial

asthma in a dose up to 600 mg of papaverine HCl daily.

N

OCH3

OCH3

H3CO

H3CO

6,7 dimethoxy-1-veratrylisoquinoline

Ethaverine A homologue of

papaverine, More potent than

papaverine

IUPAC: 1-[(3,4-diethoxyphenyl)methyl]-6,7-diethoxyisoquinoline

Amino alcohol esters

3-hydroxy-1-methylquinuclidinium bromide benzilate (Quarzan)

Marketed alone & in combination with chlordiazepoxide (Librax)

Use: peptic ulcer, hyperchlorhydria,

Dicyclomine hydrochloride (Bentyl) – binds more firmly to M1 & M3 Spasmolytic effect on SM spasms

mainly of GI tract. Useful in dysmenorrhoea, spasm of

GI tract.

ON

C2H5

C2H5O

HCl

Dicyclomine hydrochloride

2-(diethylamino)ethyl bicyclohexyl

- 1-carboxylate hydrochloride

Aminoalcohol ethers Diphenhydramine,

benztropine mesylate, orphenadrine citrate

Higher anticholinergic & low antihistaminic activity

Used as anti parkinsonian drug.

Aminoalcohols

Posses bulky grps Procyclidine HCl etc Used as

Antiparkinsonian drugs

ON

CH3

CH3CH3

Orphenadrine

Ganglionic blocking agents The Ganglionic blocking agents are drugs which

act by competition with Acetyl choline (Ach) from the cholinergic receptors present in the autonomic post ganglionic neurons.

The ganglia of both the sympathetic and parasympathetic nervous systems are cholinergic, these drugs interrupt the outflow through both system

Used mostly for their interruption of the sympathetic outflow in hypertension, vasopastic disorders and peripheral vascular disease. Thus lowering the B.P and increasing the peripheral blood flow.

Depolarizing blocking agents By prolonged depolarization e.g. Nicotine

Nondepolarising competitive GB agents MOA: Affinity to attach to nicotinic Ach receptors but no

intrinsic activity, Acts by competing with ACh for receptors

Hexamethonium, Tetraethylammonium salts, Trimethaphan camsylate.

Nondepolarizing non competetive GB agents

MOA: Produce effect not at specific receptor site but at some point far along the chain of events for impulse transmission has been imposed,. Once blocked increasing conc. Of Ach has no effect.

Mecamylamine Hydrochloride etc.

SAR n = 5-6 active as ganglionic blocker (weak

curariform activity) n = 9-12 weak GB (strong curariform activity)

Drug –Hexamethonium bromide

Trimethaphan Camsylate (Arfonad)

1,3-dibenzyldecahydro-2-oxoimidazo-4,5-thieno-1,2-thiolium-2-oxo-10-boranesulphonate

Short acting – used for neurosurgical procedures where chances of excessive bleeding may make difficulty in operative field, (moa- antihypertensive)

Indications for use: treatment of HT emergencies to reduce BP.

Mecamylamine HCl (Inversine)

N,2,3,3-tetramethy-2-norbornanamine hydrochloride

Powerful GB agent, effect same as that of hexamethonium br

Orally active. Use: moderate – severe HT (adr- severe

orthostatic hypotension

Neuromuscular blocking agents

Agents that block the transmission of Ach at the motor end plate, and bring about voluntary muscle relaxation are called NM blocking agents

Used mainly for relaxation of skeletal muscles during surgical anaesthesia.

The absence of lipophilic barrier in NMJ causes ready access to quaternary ammonium compds. Variations in quatnry str – no effect

Non-depolarising blocking agents MOA: compete with Ach for the nicotinic

receptor binding site by preventing depolarization of end plate by NT. Causes antagonistic action – no intrinsic effect

Drugs: d-Tubocurarine, dimethyltubocurarine, pancuronium and gallamine.

Tubocurarine Chloride USP

Curare alkaloids Source: Chondodendron tomentosum MOA; Competitive NM blocking, nondepolarizing blocking

agent used for its paralysing action on skeletal muscles. Action reversed by AChE inhibitors- Neostigmine, Tensilon Higher doses produce noncompetitive block Orally inactive, given as IV, action – 2 hrs. Use: As muscle relaxant in during shock therapy for mental

disorders, prevents fracture,dislocation due to convulsions produced during shock

Muscle relaxation during surgical aneathesia.

Metocurine iodide

(+)-O,O’-dimethylchondrocurarine diodide Prepared by extracting crude curare with ethanolic

KOH, and treated with methyl iodide. MOA; same as d-Tc, but more potent, and less

paralysing effect on respiration.

Papaverine alkaloids

SAR

CLASSIFICATION

Based on the mechanism these are classified as follows.1.By Interfering with Ach release - Triethyl choline, Hemicholinium

2. By interference with post synaptic action of Ach - Eg : Hexamethonium

3. By prolonged depolarization - Eg : Nicotin

O OH

NHCH3

CH3

NHCH3

CH3

OH

OH

O NH

CH3

CH3

phenethanol-amino Aryloxypropanolamines

Figure.1:the similarity in the spatial relationship of the two typical structures

Most derivatives of this series of the aryloxypropanolamines possess various substituted phenyl rings rather than the naphthyl ring. Substitution of methyl, chloro, methoxy, or nitro groups on the ring was most favored at the 2 and 3 positions and least favored in the 4 position. When dimethyl substitutions were made, the 3,5-disubstituted compound was best and the 2,6- or 2,3,6-substituted compounds show the least activity. Presumably, this was due to steric hindrance to rotation about the side chain.

Stereochemistry: Compounds with phenethenolamine structure possess high –receptor blockade when the β–C attached to the OH group is in (R) configuration. The (S)-isomer, however, has much lower activity. In the structure of Aryloxypropanolamines, the stereochemistry is just opposite to that of the former type due to the insert of an O which changes the priorities of the substituents attached to the stereogenic center (β-C). Therefore, the (S)-isomer is more active. In fact, the two types of enantiomer are consistent in the arbitrary spatial configuration. (Figure 2.)

Selectivity: Compounds with enhanced selectivity of the β1 response are characterized chiefly by para substitution rather than ortho substitution in the phenoxypropanolamine series. Practolol (our object compound), for example, is reported to inhibit the β1 receptor at lower doses than those required to inhibit the β2 receptor.

HO HNHCH(CH3)2ArO

13

4

2HO

ArNHCH(CH3)2

H1

2

3

4

(R) -isomer (S)-isomer

Figure2. the consistence in spatial configuration of the two structures

• Structure-Activity Study• A Brief Review of Pharmacology of

β-Adrenergic Blocker • Literature Information of Practolol• Route of Synthesis• The Procedure of Laboratory

Synthesis• Discussion• Reference

Effects on the Cardiovascular System: Beta-blocking drugs lower blood pressure. This effect is the result of several factors, including effects on the heart and blood vessels, the renin-angiotensin system, and possibly the central nervous system. Beta-receptor antagonists have prominent effects on the heart. The negative inotropic and chronotropic effects are predictable from the role of adrenergic receptors in regulating these functions. In the vascular system, beta-receptor blockade opposes β2-mediated effects. Beta-blocking drugs antagonize the release of renin caused by the sympathetic nervous system.

Effects on the Respiratory Tract : Blockade of the β2 receptors bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. β1 receptor-selective antagonists when blockade of β1 receptors in the heart is desired and β2 –receptor blockade is undesirable.

Effects on the Eye :Several nonselective beta-blocking agents reduce intraocular pressure, especially in glaucomatous eyes.

Effects Not Related to Beta Blockade: Partial beta-agonist activity was significant in the first beta-blocking drug synthesized. It has been suggested that retention of some intrinsic sympathomimetic activity is desirable to prevent untoward effects such as precipitation of asthma. Local anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several beta-blockers. This action is the result of typical local anesthetic blockade of sodium channels and can be demonstrated in neurons, heart muscle, and skeletal muscle membrane.

O NHCH3

CH3

R2R1

OH

O NHCH3

CH3

R2R1

OH

R1=NHCOCH2CH2CH3

R2=COCH3

R1=NHCOCH3

R2=COCH3

O NHCH3

CH3

OH

RR=NHCOCH3

acebutolol

diacetolol

practolol

• Structure-Activity Study• A Brief Review of Pharmacology of β-

Adrenergic Blocker • Literature Information of Practolol• Route of Synthesis• The Procedure of Laboratory

Synthesis• Discussion• Reference

Literature Information of Literature Information of PractololPractolol

StructureStructure ：：

CA NameCA Name ：： N-[4-[2-Hydroxy-3-[(1-N-[4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy]pheyl]acetamidemethylethyl)amino]propoxy]pheyl]acetamide

Formula and Molecular WeightFormula and Molecular Weight ：：

Physical PropertyPhysical Property ：： fine,white or almost white, ordourless powder. fine,white or almost white, ordourless powder. soluble in alcohol (1:40), slightly soluble in acetone soluble in alcohol (1:40), slightly soluble in acetone and acetic acid and acetic acid

Aqueous solution is most stable at PH6(protected from light) Aqueous solution is most stable at PH6(protected from light)

CH3CONHO NH

CH3

CH3

OH

C14H22N2O3= 266.34

• Structure-Activity Study• A Brief Review of Pharmacology of β-

Adrenergic Blocker • Literature Information of Practolol• Route of Synthesis• The Procedure of Laboratory

Synthesis• Discussion• Reference

CH3CONHO NH

CH3

CH3

OH

OHCH3CONH CH3CONH O

OO

Cl

NH2CH(CH3)2

Route of Synthesis

（Ⅰ） condensation

（Ⅱ） amination

Reagents and Apparatus

ReagentsRaw Materials: 4-acetamidophenol (impure), epichlorohydrin,

isopropylamine

Other Reagent: glacial acetate acid, alcohol absolute, activated charcoal

ApparatusApparatus for reflux: three-necked boiling flask(250ml,500ml),

mechanical stirrer, iron rings, clamps, reflux condenser,

Apparatus for vacuum filtration: Buchner funnel, suction flask, water aspirator

Apparatus for distillation: distilling flask, condenser, distillation adapter, water aspirator

Others: beakers (several ), stirring rod, drying tube, infrared light, filter paper, boiling stones

Structure-Activity Study A Brief Review of Pharmacology of β-

Adrenergic Blocker Literature Information of Practolol Route of Synthesis The Procedure of Laboratory Synthesis Discussion Reference

Condensation (the first day)

The sodium hydroxide solution(40%,w/w) was added with stirring to a mixture of 4-acetamidophenol (30g) and H2O (42.9ml) at a temperature below 25 ℃. Stirring was continued for a further 30min and there is thus obtained a clear solution with its color changing from dark blue to purple .

Epichlorohydrin was added in drops at a stable temperature slightly changing from 38℃ to 40℃. Then the reaction mixture was cooled to 35℃. A further stirring for 4h is required until milky white emulsus solid could be seen separated out from the reaction solution.

Remove the milky white emulsus solid to a flask and place it for 8 hours. The crude product was filtrated under reduced pressure. Wash it by water to PH 7 and get it dried under infrared light. There was thus obtained 1-(4-acetamidopheoxy)-2,3-epoxypropane. (31g) M.P. 110℃

The 1-(4-acetamidopheoxy)-2,3-epoxypropane (15g) and isopropylamine (42g, 62ml) were heated under reflux for 5 hours. In the initiation of the reaction the mixture appeared to be dark brown solution. After stirring for 2 hours yellow white emulsus solid was seen separate out in great quantities, with only little liquid left. An addition of about 20ml extra isopropylamine was given in order that the reaction could be thoroughly completed.

After the reaction was completed, the mixture was evaporated under reduced pressure to thoroughly recover isopropylamine.

The residue got cooled, and added in glacial acetic acid (15ml) together with 135ml water. Keep stirring for 1 hour until a solution was obtained. Add active carbon as decolorant with stirring for a further hour.

Amination (the second day)

The whole reaction system was ice-cooled to a temperature below 10℃ and underwent the vacuum filtration. The filtrate obtained was green and clear.

The filtrate was brought to PH between 8 and 9 by the addition of NaOH aqueous (35%) at the temperature between 10℃ to 20℃. Keep stirring during the process and white solid was seen separate out with NaOH added, which dissolve again once stirred. Then add the same NaOH aqueous slowly to regulate PH to 11~12 in order that crystals could separate out totally. Place it for several days to complete the aging process. The final product was obtained after further purification.

NH OH

O

CH3CCl

O

+

Reflux 12hNH O

O O

Changes made ： 1 ）

2 ）

NH OH

O

Problem arose in the first step of the synthesis of Acebutolol :

OHCH3CONH

CH3

（Ⅰ） （Ⅱ） (a kind of phenyl ester )

Problem: There was something unexpected occurred in reaction !

Descriptions in literature: The starting material were heated together under reflux until a solution formed. This solution was cooled and treated with water. The benzene layer was separated and the aqueous layer was again extracted with benzene. The extracts were dried and evaporated to dryness under reduced pressure to give (Ⅱ) as an off-white solid.

The actual phenomenon: After heating under reflux for 1 hour, the reaction mixture separated into two layers with the lower phase as kind of oil. The situation continued during the whole reflux process.

My handling Approaches:

Poured the upper layer (methyl phenyl phase) into a beaker, then white crystals separate out in large quantities. After vacuum filtration, the melting point of the crystal was measured. The result turned to be much higher than that of theoretical product (lower than100 ℃ ~105 ℃). However, It was near the M.P of acetaminophen. So I guess that it was the 4-acetamidophenol that hadn’t totally took part in the reaction.

I wanted to make sure if there was some substance soluble in the reaction solvent (methyl phenyl phase), which might be exactly the product I wanted. So I drew off the filtrate gained from last step by reduced pressure distillation. Only a few off-white solid, the M.P of which was 116 ℃ ~120 ℃, was obtained. Undoubtedly, it was not the theoretical product.

The oil-like component in the reaction mixture was insoluble in either methyl phenyl or water, but dissolved in alcohol. I tried to get the mixture heated with water and it was found that the oil turned less and softened. After heating, three layers formed: the methyl phenyl phase, the water phase and the oil. (from upper to lower) Solid separated out between the upper two layers when cooled. Extract the aqueous layer with methyl phenyl, combined the organic phase and filtrate the crystals. Repeat such operation several times to accumulate the solid. Take measure of its M.P and the value was 156 ℃, even higher than acetaminophen ! Thus I was forced to stop the synthesis of Acebutolol due to all the uncertainties above.

Analysis: I looked up some reference and organic textbooks about phenyl esters

and their reactions. It is common that compounds like phenyl ester appear to be oil-like substances, however, few exists as crystal as described in the literature of acebutolol synthesis. So now I think it’s very possible that the oil-like substance is just the product I need. One proof that supports my idea is the solid I got after heating the oil., of which the M.P is near that of pure acetaminophen, may be the hydrolyte of phenyl ester. Because heating with water is just the proper condition to generate the hydrolysis reaction. And the extraction and filtration operation made its hydrolyte (acetaminophen) greatly purified, resulting in a much higher M.P value than raw material (4- acetaminophenl) .To turn the oil-like crude product to crystal form may involve some special purification procedure that wasn’t mentioned in detail in my literature.

• William O.Foye. : Adrenergic Drugs : Principles of Medicinal Chemistry(3rd Edition) Philadelphia Lea & Febiger,1989

• Bertram G.Katzung: Adrenergic Receptor-Blocking Drugs : Basic & Clinical Pharmacology(8th Edition),Los Altos, California, LANGE Publications,1982

• B.Basil, J. R. Clark, E. C. J. Coffee, R. Jordan, A. H. Loveless, D. L. Pain, and K. R. H. Wooldridge.1976,Journal of Medecinal Chemistry 19(3):399 ～ 402

• Merck Index(11th Edition)• British Pharmaceutical Codex,1973,398 • 上海医药产品工艺汇编