1. PS postganglionic Ganglionic & Neuromuscular blocking agents
Anticholinergics
PS postganglionic
Ganglionic & Neuromuscular blocking agents

2. 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

3. 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.

4. Cholinergic Antagonists (Muscarinic receptor)
Drugs which bind to cholinergic receptor but do not activate it
Prevent acetylcholine from binding
Opposite clinical effect to agonists - lower activity of
acetylcholine
Postsynaptic
nerve
Ach
Ach
Postsynaptic
nerve
Antagonist

5. 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 

6. 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

7. Alkyl substitution in N usually methyl, ethyl, propyl, isopropyl
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.

8. 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.

9. 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

10. Therapeutic effects Mydriatic effect Antispasmodic 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 medication
Side effects: mydriasis, dryness of mouth, urinary retention
Used in treatment of Parkinson’s disease

11. 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

12. Cholinergic Antagonists (Muscarinic receptor)
Clinical Effects
Decrease of saliva and gastric secretions
Relaxation of smooth muscle
Decrease in motility of GIT and urinary tract
Dilation of pupils
Uses
Shutting down digestion for surgery
Ophthalmic examinations
Relief of peptic ulcers
Treatment of Parkinson’s Disease
Anticholinesterase poisoning
Motion sickness

13. Solanaceous alkaloids and analogs
Solanaceous Plants
Also known as the Deadly Nightshade Family.
Hyoscyamus niger
Atropa belladonna.
Datura stramonium
Have been used as poisons and hallucinogens (witches and sorcerers)

14. 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

15. 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

16. 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 ionised
analogues unable to cross the blood brain barrier No CNS side effects

17. 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
Source - roots of belladonna (1831) (deadly nightshade)
Used as a poison
Used as a medicine decreases GIT motility antidote for anticholinesterase poisoning dilation of eye pupils
CNS side effects – hallucinations

18. 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).

19. 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.

20. 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

21. 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

22. Papaverine alkaloids Papaverine- Benzylisoquinoline alkaloids
6,7 dimethoxy-1-veratrylisoquinoline
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.

23. Ethaverine A homologue of papaverine, More potent than papaverine
IUPAC: 1-[(3,4-diethoxyphenyl)methyl]-6,7-diethoxyisoquinoline

24. 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.

25. Used as Antiparkinsonian drugs Aminoalcohol ethers
Aminoalcohols
Posses bulky grps
Procyclidine HCl etc
Used as Antiparkinsonian drugs
Aminoalcohol ethers
Diphenhydramine, benztropine mesylate, orphenadrine citrate
Higher anticholinergic & low antihistaminic activity
Used as anti parkinsonian drug.

26. 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.

27. Depolarizing blocking agents Nondepolarising competitive GB 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.

28. SAR n = 5-6 active as ganglionic blocker (weak curariform activity)
n = 9-12 weak GB (strong curariform activity)
Drug –Hexamethonium bromide

29. 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.

30. 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

31. 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

32. 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.

33. 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.

34. 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.

35. Papaverine alkaloids

36. SAR

38. 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

39. phenethanol-amino
Aryloxypropanolamines
Figure.1:the similarity in the spatial relationship of the two typical structures

40. 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.)

41. (R) -isomer
(S)-isomer
Figure2. the consistence in spatial configuration of the two structures
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.

42. Catalogue 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

43. Pharmcologic Study
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.

44. 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.

45. Decision making in choosing object compound
acebutolol
diacetolol
practolol

46. Catalogue 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

47. Literature Information of Practolol
Structure：
CA Name：N-[4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy]pheyl]acetamide
Formula and Molecular Weight：
Physical Property：fine,white or almost white, ordourless powder soluble in alcohol (1:40), slightly soluble in acetone and acetic acid
Aqueous solution is most stable at PH6(protected from light)

48. Catalogue 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

49. Route of Synthesis
（Ⅰ）condensation
（Ⅱ）amination

50. Reagents and Apparatus
Raw Materials: 4-acetamidophenol (impure), epichlorohydrin, isopropylamine
Other Reagent: glacial acetate acid, alcohol absolute, activated charcoal
Apparatus
Apparatus 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

51. Catalogue 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

52. the Laboratory Synthesis of Practolol
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℃

53. Amination (the second day)
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.

54. 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.

55. Problem Discussion
Problem arose in the first step of the synthesis of Acebutolol :
Reflux 12h
（Ⅰ）
（Ⅱ）(a kind of phenyl ester )
Changes made： 1） 2）

56. 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.

57. 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.

58. 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.

59. Reference
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
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