Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations


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

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 ©

6 1 © Cycloplegia Cycloplegia is the paralysis of the ciliary muscle, resulting in a loss of accommodation. Cycloplegic drugs, including atropine, cyclopentolate, succinylcholine, homatropine, scopolamine and tropicamide, are indicated for use in cycloplegic refractions and the treatment of uveitis. Other cycloplegic drugs include Neostigmine, Phentolamine and Pilocarpine mydriasis Mydriasis Classifications and external resources An abnormally dilated pupil. Mydriasis is an excessive dilation of the pupil due to disease or drugs. Although the pupil will normally dilate in the dark, it is usually quite constricted in the light. A mydriatic pupil will remain excessively large, even in a bright environment. Constriction of the pupil is called miosis

7 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)

8 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)

9 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)

10 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)

11 1 © 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 β 2 -agonists:Salbutamol, Terbutaline Long acting β 2 -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 Diphenoxylate is an opioid agonist used for the treatment of diarrhea that acts by slowing intestinal contractions. It was discovered at Janssen Pharmaceutica in It is a congener to the narcotic Meperidine of which the common brand name is Demerol. This being the case, this medication is potentially habit-forming, particularly in high doses or when long-time usage is involved. Because of this, diphenoxylate is manufactured and marketed as a combination drug with atropine (Lomotil®). This pharmaceutical strategy is designed to discourage abuse, because the anticholinergic effect of atropine will produce severe weakness and nausea if standard dosage is exceeded. This medication is classified as a Schedule V under the Controlled Substances Act by the Food and Drug Administration (FDA) and the DEA in the United States when used in preparations. When diphenoxylate is used alone, it is classified as a Schedule II.

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

13 1 © 12.5 Simplified Analogues Tropicamide (opthalmics) Cyclopentolate (opthalmics) Benztropine (Parkinsons disease) Benzhexol (Parkinsons disease) Pirenzepine (anti-ulcer) 12. Cholinergic Antagonists (Muscarinic receptor)

14 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)

15 1 ©InactiveActive 12.6 SAR for Antagonists 12. Cholinergic Antagonists (Muscarinic receptor)

16 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)

17 1 © RECEPTOR SURFACE Acetylcholine binding site 12.7 Binding Site for Antagonists van der Waals binding regions for antagonists 12. Cholinergic Antagonists (Muscarinic receptor)

18 1 © 12.7 Binding Site for Antagonists 12. Cholinergic Antagonists (Muscarinic receptor)

19 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

20 1 © Tubocurarine chloride is a competitive antagonist of nicotinic neuromuscular acetylcholine receptors, used to paralyse patients undergoing anaesthesia. 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. The correct chemical structure was only elucidated circa 1970, even though the plant had been known since the Spanish Conquest. The word curare comes from the South American Indian name for the arrow poison: "ourare". Presumably the initial syllable was pronounced with a heavy glottal stroke. Tubocurarine is so called because the plant samples containing it were first shipped to Europe in tubes. Today, tubocurarine has fallen into disuse in western medicine, as safer synthetic alternatives such as atracurium are available. However, tubocurarine is still used in the United States and elsewhere as part of the lethal injection procedure.

21 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

22 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)

23 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)

24 1 © Suxamethonium chloride From Wikipedia, the free encyclopedia (Redirected from Succinylcholine) RoutesIntravenous Suxamethonium chloride (also known as succinylcholine, scoline, or SUX) is a white crystalline substance, it is odourless and highly soluble in water. The compound consists of two acetylcholine molecules that are linked by their acetyl groups. Suxamethonium is sold under several trademark names such as Anectine®, and may be referred to as "sux" for short. Suxamethonium acts as a depolarizing muscle relaxant. It imitates the action of acetylcholine at the neuromuscular junction, but it is not degraded by acetylcholinesterase but by pseudocholinesterase, a plasma cholinesterase. This hydrolysis by pseudocholinesterase is much slower than that of acetylcholine by acetylcholinesterase.lcholinesterase. There are two phases to the blocking effect of suxamethonium. The first is due to the prolonged stimulation of the acetylcholine receptor results first in disorganized muscle contractions (fasciculations, considered to be a side effect as mentioned below), as the acetylcholine receptors are stimulated. On stimulation, the acetylcholine receptor becomes a general ion channel, so there is a high flux of potassium out of the cell, and of sodium into the cell, resulting in an endplate potential less than the action potential. So, after the initial firing, the cell remains refractory. i

25 1 © On continued stimulation, the acetylcholine receptors become desensitised and close. This means that new acetylcholine signals do not cause an action potential; and the continued binding of suxamethonium is ignored. This is the principal anaesthetic effect of suxamethonium, and wears off as the suxamethonium is degraded, and the acetylcholine receptors return to their normal configuration. The side effect of hyperkalaemia is because the acetylcholine receptor is propped open, allowing continued flow of potassium ions into the extracellular fluid. A typical increase of potassium ion serum concentration on administration of suxamethonium is 0.5 mmol per litre, whereas the normal range of potassium is 3.5 to 5 mmol per litre: a significant increase which results in the other side-effects of ventricular fibrillation due to reduced to action potential initiation in the heart. Its medical uses are limited to short-term muscle relaxation in anesthesia and intensive care, usually for facilitation of endotracheal intubation. Despite its many undesired effects on the circulatory system and skeletal muscles (including malignant hyperthermia, a rare but life-threatening disease), it is perennially popular in emergency medicine because it arguably has the fastest onset and shortest duration of action of all muscle relaxants. Both are major points of consideration in the context of trauma care, where paralysis must be induced very quickly and the use of a longer-acting agent might mask the presence of a neurological deficit. A single intravenous dose of 1.0 to 1.5 milligrams per kilogram of body weight for adults or 2.0 milligrams per kilogram for pediatrics will cause flaccid paralysis within a minute of injection. For intramuscular injection higher doses are used and the effects last somewhat longer. Suxamethonium is quickly degraded by plasma cholinesterase and the duration of effect is usually in the range of a few minutes. When plasma levels of cholinesterase are greatly diminished or an atypical form of cholinesterase is present (an otherwise harmless inherited disorder), paralysis may last much longer. Suxamethonium chloride

26 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)

27 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)

28 1 © Atracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarising neuromuscular blocking agents, used adjunctively in anaesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Side effects owing to histamine liberation are rash, reflex increase in heart rate, low blood pressure and bronchospasm. It is a bisbenzyltetrahydroisoquinolinium mixture of 10 Stereoisomers. Atracurium was first synthesized, in 1974 by George H. Dewar, in John B. Stenlake's medicinal chemistry research group at Strathclyde University, Scotland. It is the first non- depolarising non-steroidal skeletal muscle relaxant rationally designed to undergo chemodegradation in vivo. Atracurium was licensed to Burroughs Wellcome Co., which developed atracurium and eventually marketed it (as a mixture of all ten stereoisomers)under the name Tracrium. Atracurium's rate of degradation in vivo is influenced by pH and temperature. Atracurium was succeeded by cisatracurium, which is the R-cis R-cis isomer constituent of atracurium. The pharamcodynamic and adverse effect profile of cisatracurium proved to be superior to that of atracurium. Cisatracurium was made available worldwide as Nimbex, with its clinical development solely undertaken by Burroughs Wellcome Co. Atracurium is classified as an intermediate-acting neuromuscular blocking agent.

29 1 © Atracurium Pharmacokinetic data Bioavailability100% (IV) Protein binding82% MetabolismHoffman elimination (retro-Michael addition) and ester hydrolysis Half life17-21 minutes Excretion ? RoutesIV Atracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarising neuromuscular blocking agents, used adjunctively in anaesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Side effects owing to histamine liberation are rash, reflex increase in heart rate, low blood pressure and bronchospasm. It is a bisbenzyltetrahydroisoquinolinium mixture of 10 Stereoisomers. Atracurium was first synthesized, in 1974 by George H. Dewar, in John B. Stenlake's medicinal chemistry research group at Strathclyde University, Scotland. It is the first non-depolarising non-steroidal skeletal muscle relaxant rationally designed to undergo chemodegradation in vivo. Atracurium was licensed to Burroughs Wellcome Co., which developed atracurium and eventually marketed it (as a mixture of all ten stereoisomers)under the name Tracrium. Atracurium's rate of degradation in vivo is influenced by pH and temperature. Atracurium was succeeded by cisatracurium, which is the R-cis R-cis isomer constituent of atracurium. The pharamcodynamic and adverse effect profile of cisatracurium proved to be superior to that of atracurium. Cisatracurium was made available worldwide as Nimbex, with its clinical development solely undertaken by Burroughs Wellcome Co. Atracurium is classified as an intermediate-acting neuromuscular blocking age

30 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)

31 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)


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

Similar presentations


Ads by Google