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

2. 1 © Contents 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. 1 © 12. 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 ofOpposite clinical effect to agonists - lower activity ofacetylcholine Postsynaptic nerve Ach Antagonist Ach Postsynaptic nerve Ach

4. 1 © 12. Cholinergic Antagonists (Muscarinic receptor) Clinical Effects Decrease of saliva and gastric secretionsDecrease of saliva and gastric secretions Relaxation of smooth muscleRelaxation of smooth muscle Decrease in motility of GIT and urinary tractDecrease in motility of GIT and urinary tract Dilation of pupilsDilation of pupils Uses 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

5. 1 © 12.1 Atropine Racemic form of hyoscyamineRacemic 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 decreases GIT motility antidote for anticholinesterase poisoning dilation of eye pupilsUsed as a medicine decreases GIT motility antidote for anticholinesterase poisoning dilation of eye pupils CNS side effects - hallucinationsCNS side effects - hallucinations easily racemised 12. Cholinergic Antagonists (Muscarinic receptor)

6. 1 © 12.2 Hyoscine (scopolamine) Source - thorn appleSource - thorn apple Medical use - treatment of motion sicknessMedical use - treatment of motion sickness Used as a truth drug (CNS effects)Used as a truth drug (CNS effects) 12. Cholinergic Antagonists (Muscarinic receptor)

7. 1 © 12.3 Comparison of atropine with acetylcholine Relative positions of ester and nitrogen similar in both moleculesRelative positions of ester and nitrogen similar in both molecules Nitrogen in atropine is ionisedNitrogen in atropine is ionised Amine and ester are important binding groups (ionic + H-bonds)Amine and ester are important binding groups (ionic + H-bonds) Aromatic ring of atropine is an extra binding group (vdW)Aromatic ring of atropine is an extra binding group (vdW) Atropine binds with a different induced fit - no activationAtropine binds with a different induced fit - no activation Atropine binds more strongly than acetylcholineAtropine binds more strongly than acetylcholine 12. Cholinergic Antagonists (Muscarinic receptor)

8. 1 © 12.4 Analogues of atropine Analogues are fully ionisedAnalogues are fully ionised Analogues unable to cross the blood brain barrierAnalogues unable to cross the blood brain barrier No CNS side effectsNo CNS side effects Atropine methonitrate (lowers GIT motility) Ipratropium (bronchodilator & anti-asthmatic) 12. Cholinergic Antagonists (Muscarinic receptor)

9. 1 © 12.5 Simplified Analogues Pharmacophore = ester + basic amine + aromatic ring Amprotropine Tridihexethyl bromide Propantheline chloride 12. Cholinergic Antagonists (Muscarinic receptor)

10. 1 © 12.5 Simplified Analogues Tropicamide (opthalmics) Cyclopentolate (opthalmics) Benztropine (Parkinsons disease) Benzhexol (Parkinsons disease) Pirenzepine (anti-ulcer) 12. Cholinergic Antagonists (Muscarinic receptor)

11. 1 © 12.6 SAR for Antagonists Important features Tertiary amine (ionised) or a quaternary nitrogenTertiary amine (ionised) or a quaternary nitrogen Aromatic ringAromatic ring EsterEster N-Alkyl groups (R) can be larger than methyl (unlike agonists)N-Alkyl groups (R) can be larger than methyl (unlike agonists) Large branched acyl groupLarge branched acyl group R’ = aromatic or heteroaromatic ringR’ = aromatic or heteroaromatic ring Branching of aromatic/heteroaromatic rings is importantBranching of aromatic/heteroaromatic rings is important R' = Aromatic or Heteroaromatic 12. Cholinergic Antagonists (Muscarinic receptor)

12. 1 ©InactiveActive 12.6 SAR for Antagonists 12. Cholinergic Antagonists (Muscarinic receptor)

13. 1 © 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 Quaternary nitrogen Aromatic ring Ester N-Alkyl groups = methyl R’ = H SAR for Antagonists SAR for Agonists 12.6 SAR for Antagonists vs. Agonists 12. Cholinergic Antagonists (Muscarinic receptor)

14. 1 © RECEPTOR SURFACE Acetylcholine binding site 12.7 Binding Site for Antagonists van der Waals binding regions for antagonists 12. Cholinergic Antagonists (Muscarinic receptor)

15. 1 © 12.7 Binding Site for Antagonists 12. Cholinergic Antagonists (Muscarinic receptor)

16. 1 © 13. Cholinergic Antagonists (Nicotinic receptor) 13.1 Curare Extract from ourari plantExtract from ourari plant Used for poison arrowsUsed for poison arrows Causes paralysis (blocks acetylcholine signals to muscles)Causes paralysis (blocks acetylcholine signals to muscles) Active principle = tubocurarineActive principle = tubocurarine Tubocurarine

17. 1 © 13. Cholinergic Antagonists (Nicotinic receptor) Pharmacophore Two quaternary centres at specific separation (1.15nm)Two quaternary centres at specific separation (1.15nm) Different mechanism of action from atropine based antagonistsDifferent mechanism of action from atropine based antagonists Different binding interactionsDifferent binding interactions Clinical uses Neuromuscular blocker for surgical operationsNeuromuscular blocker for surgical operations Permits lower and safer levels of general anaestheticPermits lower and safer levels of general anaesthetic Tubocurarine used as neuromuscular blocker but side effectsTubocurarine used as neuromuscular blocker but side effects

18. 1 © 13.2 Binding a) Receptor dimer S b) Interaction with tubocurarine protein complex (5 subunits) diameter=8nm 8nm 9-10nm Tubocurarine Acetylcholine binding site 13. Cholinergic Antagonists (Nicotinic receptor)

19. 1 © 13.3 Analogues of tubocurarine Long lastingLong lasting Long recovery timesLong recovery times Side effects on heartSide effects on heart Esters incorporatedEsters incorporated Shorter lifetime (5 min)Shorter lifetime (5 min) Fast onset and short durationFast onset and short duration Side effects at autonomic gangliaSide effects at autonomic ganglia Decamethonium Suxamethonium 13. Cholinergic Antagonists (Nicotinic receptor)

20. 1 © 13.3 Analogues of tubocurarine Steroid acts as a spacer for the quaternary centres (1.09nm)Steroid acts as a spacer for the quaternary centres (1.09nm) Acyl groups are added to introduce the Ach skeletonAcyl groups are added to introduce the Ach skeleton Faster onset then tubocurarine but slower than suxamethoniumFaster onset then tubocurarine but slower than suxamethonium Longer duration of action than suxamethonium (45 min)Longer duration of action than suxamethonium (45 min) No effect on blood pressure and fewer side effectsNo effect on blood pressure and fewer side effects 13. Cholinergic Antagonists (Nicotinic receptor) Pancuronium (R=Me) Vecuronium (R=H)

21. 1 © 13.3 Analogues of tubocurarine Design based on tubocurarine and suxamethoniumDesign based on tubocurarine and suxamethonium Lacks cardiac side effectsLacks cardiac side effects Rapidly broken down in blood both chemically and metabolicallyRapidly broken down in blood both chemically and metabolically Avoids patient variation in metabolic enzymesAvoids patient variation in metabolic enzymes Lifetime is 30 minutesLifetime is 30 minutes Administered as an i.v. dripAdministered as an i.v. drip Self destruct system limits lifetimeSelf destruct system limits lifetime Atracurium 13. Cholinergic Antagonists (Nicotinic receptor)

22. 1 © 13.3 Analogues of tubocurarine Atracurium stable at acid pH Hofmann elimination at blood pH (7.4) ACTIVE INACTIVE 13. Cholinergic Antagonists (Nicotinic receptor)

23. 1 © 13.3 Analogues of tubocurarine Mivacurium Faster onset (2 min)Faster onset (2 min) Shorter duration (15 min)Shorter duration (15 min) 13. Cholinergic Antagonists (Nicotinic receptor)