1. CHOLINERGICS, ANTICHOLINERGICS & ANTICHOLINESTERASES
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 19
CHOLINERGICS, ANTICHOLINERGICS
& ANTICHOLINESTERASES
Part 2: Cholinergics & anticholinesterases

2. Contents
Part 2: Cholinergics & anticholinesterases
12. Cholinergic Antagonists (Muscarinic receptor) (2 slides)
12.1. Atropine
12.2. Hyoscine (scopolamine)
12.3. Comparison of atropine with acetylcholine
12.4. Analogues of atropine
12.5. Simplified Analogues (2 slides)
12.6. SAR for Antagonists (3 slides)
12.7. Binding Site for Antagonists (2 slides)
13. Cholinergic Antagonists (Nicotinic receptor)
13.1. Curare (2 slides)
13.2. Binding
13.3. Analogues of tubocurarine (5 slides)
[22 slides]

3. 12. 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

4. 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

5. 12. Cholinergic Antagonists (Muscarinic receptor)
12.1 Atropine
easily racemised
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
Link

6. Opthalmic use of atropine a as mydriatic (dilating) agent has been largely replaced by use of analogs tropicamide and cyclopenatolate (vida infra).
However, atropine, and its chiral analog hyoscyamine, are utilized to treat gastrointestinal disorders
Also these antagonists can be used to treat the symptoms of an excess of acetylcholine, such as might occur upon exposure to an inhibitor of the enzyme acetylcholinesterase (such as a nerve gas). Link

7. Atropine is also used to avoid bradycardia (too slow heart rate) during some procedures (such as pediatric RSI, rapid sequence intubation), which also use succinylcholine (suxamethonium chloride) as a neuromuscular blocking agent (antagonist at the nicotinic Ach receptors).
As shown in the diagram above, the atropine serves as an antagonist of acetycholine at the M2 receptor of the sinoatrial node.
The acetylcholine at this junction triggers a GPCR using the Gi G-protein, normally leading to decrease in the levels of cAMP. Thus the atropine restores normal levels of cAMP, reversing the effects of vagus nerve stimulation.

8. 12. Cholinergic Antagonists (Muscarinic receptor)
12.2 Hyoscine (scopolamine)
Source - thorn apple
Medical use - treatment of motion sickness
Used as a truth drug (CNS effects)

9. Hyoscine (Scopolamine)

10. 12. Cholinergic Antagonists (Muscarinic receptor)
12.3 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

11. 12. Cholinergic Antagonists (Muscarinic receptor)
12.4 Analogues of atropine
Ipratropium
(bronchodilator & anti-asthmatic)
Atropine methonitrate
(lowers GIT motility)
Analogues are fully ionised
Analogues unable to cross the blood brain barrier
No CNS side effects

12. The combination preparation ipratropium/salbutamol is a formulation containing ipratropium bromide and salbutamol sulfate (albuterol sulfate) used in the management of chronic obstructive pulmonary disease (COPD) and asthma. It is marketed by Boehringer Ingelheim as metered dose inhaler (MDI) and nebuliser preparations under the trade name Combivent.
Medications commonly used in asthma and COPD (primarily R03) edit
Anticholinergics: Ipratropium, Tiotropium
Short acting β2-agonists: Salbutamol, Terbutaline
Long acting β2-agonists (LABA): Bambuterol, Clenbuterol, Fenoterol, Formoterol, Salmeterol
Corticosteroids: Beclometasone, Budesonide, Ciclesonide, Fluticasone
Leukotriene antagonists: Montelukast, Pranlukast, Zafirlukast
Xanthines: Aminophylline, Theobromine, Theophylline
Mast cell stabilizers: Cromoglicate, Nedocromil
Combination products: Budesonide/formoterol, Fluticasone/salmeterol, Ipratropium/salbutamol

13. 12. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Pharmacophore = ester + basic amine + aromatic ring
Tridihexethyl bromide
Amprotropine
Propantheline chloride

14. 12. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Benztropine
(Parkinsons disease)
Tropicamide
(opthalmics)
Cyclopentolate
(opthalmics)
Pirenzepine
(anti-ulcer)
Benzhexol
(Parkinsons disease)

15. Cyclopentolate
Tropicamide
Tropicamide and Cyclopentolate (above) are among the most commonly employed mydriatic (dilating) and cycloplegic (paralyzing) agents
Both function as antagonists at the muscarinic acetylcholine receptors

16. 12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists
R' = Aromatic or
Heteroaromatic
Important features
Tertiary amine (ionised) or a quaternary nitrogen
Aromatic ring
Ester
N-Alkyl groups (R) can be larger than methyl (unlike agonists)
Large branched acyl group
R’ = aromatic or heteroaromatic ring
Branching of aromatic/heteroaromatic rings is important

17. 12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists
Inactive
Active

18. 12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists vs. Agonists
SAR for Antagonists
SAR for Agonists
Quaternary nitrogen
Aromatic ring
Ester
N-Alkyl groups = methyl
R’ = H
Tertiary amine (ionised)
or quaternary nitrogen
Aromatic ring
Ester
N-Alkyl groups (R) can be
larger than methyl
R’ = aromatic or heteroaromatic
Branching of Ar rings important

19. 12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists
RECEPTOR SURFACE
Acetylcholine
binding site
van der Waals
binding regions
for antagonists

20. 12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists

21. 13. Cholinergic Antagonists (Nicotinic receptor)
13.1 Curare
Extract from ourari plant
Used for poison arrows
Causes paralysis (blocks acetylcholine signals to muscles)
Active principle = tubocurarine
Tubocurarine

22. Tubocurarine chloride is a competitive antagonist of nicotinic neuromuscular acetylcholine receptors, It is one of the chemicals that can be obtained from curare, itself an extract of Chondodendron tomentosum, a plant found in South American jungles which is used as a source of arrow poison. Native indians hunting animals with this poison were able to eat the animal's contaminated flesh without being affected by the toxin because tubocurarine cannot easily cross mucous membranes and is thus inactive orally.

23. Tubocurarine began to be clinically utilized as a surgical neuromuscular blocking agent in the 1940’s
This drug has been supplanted by safer medicines, but is still utilized as part of the lethal injection procedure.

24. 13. Cholinergic Antagonists (Nicotinic receptor)
Pharmacophore
Two quaternary centres at specific separation (1.15nm)
Different mechanism of action from atropine based antagonists
Different binding interactions
Clinical uses
Neuromuscular blocker for surgical operations
Permits lower and safer levels of general anaesthetic
Tubocurarine used as neuromuscular blocker but side effects

25. 13. Cholinergic Antagonists (Nicotinic receptor)
13.2 Binding S
b) Interaction with tubocurarine
protein complex
(5 subunits)
diameter=8nm
8nm
a) Receptor dimer
9-10nm
Tubocurarine
Acetylcholine binding site

26. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Decamethonium
Long lasting
Long recovery times
Side effects on heart
No longer in clinical use

27. Suxamethonium
(Succinylcholine)
Esters incorporated
Shorter lifetime (5 min)
Fast onset and short duration
Frequently used during intubation
Side effects at autonomic ganglia

28. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Pancuronium (R=Me)
Vecuronium (R=H)
Steroid acts as a spacer for the quaternary centres (1.09nm)
Acyl groups are added to introduce the Ach skeleton
Faster onset then tubocurarine but slower than suxamethonium
Longer duration of action than suxamethonium (45 min)
No effect on blood pressure and fewer side effects

29. Pancuronium is used to block the neuromuscular junction during surgery or intubation.
In the US, pancuronium (pavulon) is the second of three drugs used in execution by lethal injection
Lawsuits against the lethal injection procedure have charged that this drug would make the patient unable to cry out if he was in pain, as might occur if insufficient sodium thiopentol (the anesthetic) had been administered

30. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Atracurium
Design based on tubocurarine and suxamethonium
Lacks cardiac side effects
Rapidly broken down in blood both chemically and metabolically
Avoids patient variation in metabolic enzymes
Lifetime is 30 minutes
Administered as an i.v. drip
Self destruct system limits lifetime

31. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
INACTIVE
ACTIVE
Atracurium stable at acid pH
Hofmann elimination at blood pH (7.4)

32. An improved version of atracurium is the purified form of just one of the ten possible stereoisomers, that has the highest efficacy and least side effects
The name of the blocking agent is cisatracurium (NIMBEX)
This is the most widely used agent surgically.
80% of the drug is metabolized via Hofmann elimination, thus lowering variability in patients with possible liver or renal disease.
The Hofmann degradation is only dependent on the pH and temperature of the plasma.

33. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Mivacurium
Faster onset (2 min)
Shorter duration (15 min)

34. The use of mivacurium has declined in recent years, in favor of other agents with better overall profile.

35. Assigned Reading
Introduction to Medicinal Chemistry by Graham L. Patrick, Chapter 19, pp
Bowman, W. C.. Neuromuscular block. British Journal of Pharmacology (2006), 147(Suppl. 1), S277-S286.

36. Homework Questions:
Briefly describe the differences between the sympathetic and parasympathetic divisions of the autonomic nervous system, including the neurotransmitter used at the respective neuromuscular junctions.
Cholinergic receptors are divided into nicotinic and muscarinic classes. How are these receptors different? Draw the structures of nicotine and muscarine and show how they might resemble the natural agonist, acetylcholine.
Methacholine, carbachol, and bethanechol are acetylcholine agonists at the muscarinic receptor. Draw the structure of each and explain the rationale behind the structural modifications. Describe how each agonist is used clinically.
Atropine and scopolamine (hyocine) are cholinergic antagonists at the muscarinic receptors. Draw their structures, illustrate the structural resemblance to acetylcholine, and describe their clinical utility.

37. Describe the difference between a nondepolarising blocking drug and a depolarizing blocking drug. Provide an example of each.
Describe the ‘safe’ technique of ‘balanced anesthesia’.
What is the depolarizing drug, suxamethonium, used for? Why is its utility limited?
Why are atracurium (and its single stereoisomer, cis-atracurium) valuable as neuromuscular blocking agents during surgery? Draw its structure. What structural feature is important to limiting their half life in vivo?